A Jeffrey, Associate Professor
Childrens Hospital Of Philadelphiacity: Philadelphia country: United States (us)
Abstract: The initial (1999) application for this IDDRC included separate cores in Neuropathology and Neuroscience, with the latter offering expertise in cell culture. As user needs evolved, it became apparent that these facilities should be merged into a single Cellular Neuroscience Core. This was accomplished in 1994 with Dr. Pleasure as the Director. He served in this capacity unfil 2001, when leadership passed to Dr. Jeffrey Golden, a pediatric neuropathologist with a primary interest in developmental disorders. Dr. Golden first joined CHOP in 1997 and immediately became engaged with the IDDRC, both as a user and as an Associate Director of the Cellular Neuroscience Core. Since its inception this Core has provided users with a diverse repertoire of state-of-the-art methods for visualizaion of the distribufions of gene products in normal, developing neural cells and in those undergoing various forms of degeneration and regenerafion. We have confinually and eagerly added new skills, instrumentafion and reagents to better serve our users´ needs. In 1995, with the generous assistance of the Children´s Hospital, we purchased a Leica confocal microscope to which we added inverted microscopy, stagemounted micromanipulators/microinjectors, and a stage-mounted environmental chamber, thus permitting prolonged observation and manipulation of living cells under physiological conditions. In this manner we offered 8-color capacity fluorescent imaging. Our institution paid for the apparatus and we used IDDRC funding to partially support a technician. We made several other notable technological additions to the Core repertoire, including in situ hybridization in both sections and whole embryos. Our general purpose has been not only to make available a technology, but a consultative sen/ice that facilitates implementation of the method as well as the interpretation of data. We adhered to this policy when we also added video-enhanced microscopy in order to better support IDDRC investigators in analyzing intracellular Ca2+ and Na+ as well as the estimate of mitochondrial potential
Keywords: Animals; Biochemistry; Brain; Cell Culture Techniques; Cell physiology; Cells; Childhood; Color; Counseling; Data; Development; Developmental Disabilities; developmental disease/disorder; disability; Disease; Embryo; Ensure; experience; Functional disorder; Funding; Goals; Human; Human Resources; Ice; Image; In Situ Hybridization; innovation; Institution; Intellectual functioning disability; interest; Leadership; Life; Mental Retardation and Developmental Disabilities Research Centers; Methods; micromanipulator; Microscope; Microscopy; Mitochondria; Molecular; Neurons; neuropathology; Neurosciences; novel; Pediatric Hospitals; Physiological; pleasure; Policies; Preparation; Productivity; Proteins; Reagent; Research; Research Personnel; response; Series; skills; Specimen; Staging; Stem cells; Surveys; Techniques; Technology
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5P30HD026979-22_8152 (2011): $166057
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to A Jeffrey
ELECTRICAL, MOLECULAR AND CLINICAL CORRELATES OF HUMAN INTERICTAL SPIKING
A Jeffrey, Associate Professor
Wayne State Universitycity: Detroit country: United States (us)
Grant 5R01NS058802-04 from National Institute Of Neurological Disorders And Stroke
Abstract: We have taken a functional genomic approach to ask what is different between nearby regions of electrically-mapped human neocortex removed surgically for the treatment of medically refractory epilepsy. We identified a small group of genes that are significantly induced at epileptic foci in almost all patients examined, regardless of underlying lesion. For the first time now, we have highly reliable molecular markers of epileptic neocortex that point to a specific signaling pathways and populations of neurons that characterize neocortical epileptic foci. While it is still not clear whether the induction of these genes are a consequence or a driving force of abnormally firing neurons, we found that the induction of many of these genes correlate precisely with the degree interictal spiking suggesting that the molecular pathways identified and interictal spiking are closely related. In this proposal, we will measure a group of quantitative parameters of interictal spiking from the neocortex of patients undergoing epilepsy surgery and relate these to the generation of seizures and the underlying gene expression and signaling pathways. These will be placed within the 3-dimensional structure of the human brain to ask further questions about the human brain´s infoldings on human epilepsy. One long-term goal for this project is to develop an understanding of the clinical significance of interictal spiking to help guide future clinical decisions. Another goal is to understand the relationships between electrical activity with molecular and cellular pathways that will help us develop new, biologically-driven, diagnostics and therapeutics for human epilepsy. Epilepsy is a common neurological disorder affecting up to 1% of the world´s population. It is one of the least understood disorders that can develop after a wide range of brain insults. At present, there are no treatments to prevent epilepsy, and while existing medications reduce seizure frequency, they do not "cure" the disorder. It is possible to "cure" epilepsy by removing electrically-defined epileptic foci. Removal of these focal brain regions also presents an opportunity to discover the molecular and cellular basis of human epilepsy in a way that cannot be achieved in animal models. The improved methods we develop to measure spiking and the molecular and clinical correlates of interictal spiking will have great utility both for clinical management of patients with epilepsy and for the development of novel, targeted treatment and diagnostic strategies
Keywords: 3-Dimensional; Affect; Animal Model; Architecture; Area; base; Brain; Brain region; Cells; Clinical; Clinical Management; clinically significant; Complex; CREB1 gene; Development; Diagnostic; Disease; driving force; Electrodes; Epilepsy; Excision; Frequencies (time pattern); functional genomics; Future; Gene Expression; gene induction; Generations; Genes; Goals; Health; Human; improved; interest; Lesion; Magnetic Resonance Imaging; Maintenance; MAP Kinase Gene; Maps; Measures; Methods; Molecular; molecular marker; Molecular Profiling; Neocortex; neocortical; nervous system disorder; Neurons; novel; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Population; prevent; Principal Investigator; Process; programs; reconstruction; Recurrent disease; Refractory; Seizures; Signal Pathway; Signaling Pathway Gene; Testing; Therapeutic; three dimensional structure; Time; Tissues; tool; transcription factor; Western Blotting; Work
Project start date: 2008-06-01
Project end date: 2013-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-07-070
5R01NS058802-04 (2011): $322498
CD180(RP105) REGULATION OF TLR AND BCR RESPONSES IN B CELLS
A Jeffrey, Research Professor
University Of Washingtoncity: Seattle country: United States (us)
Grant 5R21AI085311-02 from National Institute Of Allergy And Infectious Diseases
Abstract: This proposal will investigate the potential for B cell immunoregulation by CD180 stimulation and study the mechanisms of CD180 interactions with BCR and TLR signals. CD180 (RP105) expression is required for TLR4 and TLR2-mediated B cell proliferation and T cell- independent antibody responses (TI-1 response). We propose a comprehensive study of the CD180 receptor, including studies of the mechanisms of CD180 interaction with BCR and TLR signals, combined with analysis of CD180 activation in mice to determine the effect on antigen-specific B cells expressing transgenic high affinity BCR (B1-8hi) specific for NP, and on the antibody response to NP-CGG. These experiments will determine whether CD180 activation may serve as a sensitization signal that could result in selective B cell deletion upon antigen binding. CD180 is thought to coordinate or integrate the TLR4 and TLR2 signals with BCR signals in B cells to drive an antigen specific antibody response of all isotypes. We have found that CD180 stimulation together with TLR agonists results in synergistic B cell proliferation, and augments B cell production of inflammatory cytokines IL-6, IL-10, and TNF1. In contrast, proliferation of CD180-stimulated B cells is inhibited by simultaneous BCR stimulation, and CD180-activated B cells are sensitized to anti-BCR apoptosis. The second major component of this grant will use molecular engineering of soluble forms of CD180/MD-1 that are expressed in mammalian cells to help identify and potentially block natural CD180 ligands. We will also express anti-human and anti-mouse CD180 scFv-Ig fusion proteins. The scFvs will be constructed with wt or mutated human and mouse Ig tails in order to study the regulation of CD180 signals by FcR binding. The results will help clarify the role of CD180 as a master regulator of TLR2 and TLR4 and will help determine the potential for CD180 as a target for antibody-based therapy. The work will also result in construction and expression of recombinant molecules that will be useful in future studies of CD180 therapy in infectious disease and cancer models. CD180 is a critical receptor for regulation of TLR4 and TLR2 function in B cells and could be an important target for immunoregulation. This grant will express recombinant molecules for CD180 stimulation and will test the potential for CD180 as a therapeutic target for deletion of autoreactive B cells
Keywords: Affinity; Agonist; Antibodies; Antibody Formation; antigen binding; Antigens; Apoptosis; autoreactive B cell; B Cell Proliferation; B-Lymphocytes; base; Binding (Molecular Function); Cancer Model; Cell Line; Cessation of life; Chimeric Proteins; Complex; Couples; cytokine; Data; design and construction; dimer; Engineering; Fc domain; Future; Goals; Grant; Human; IgG3; Immunoglobulin Variable Region; Immunomodulators; immunoregulation; In Vitro; in vivo; infectious disease model; Inflammatory; Injection of therapeutic agent; Interleukin-10; Interleukin-6; Lead; Ligands; Link; Mammalian Cell; Mediating; Membrane; Molecular; Mus; Mutate; novel; Production; Proteins; public health relevance; receptor; Receptor Signaling; Receptors, Antigen, B-Cell; Recombinants; Regulation; research study; response; Role; Serum; Signal Transduction; Signal Transduction Pathway; T-Lymphocyte; Tail; tandem mass spectrometry; Testing; therapeutic target; TLR2 gene; TLR4 gene; TNF gene; tool; Toxic effect; Transgenic Mice; Transgenic Organisms; Tyrosine Phosphorylation; Work
Project start date: 2010-05-01
Project end date: 2012-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-06-181
5R21AI085311-02 (2011): $175500
CLINICAL INVESTIGATION IN TUMOR IMMUNOTHERAPY
A Jeffrey
Vanderbilt Universitycity: Nashville country: United States (us)
Grant 5K24CA097588-09 from National Cancer Institute
Abstract: This proposal is the competitive renewal of a K24, Midcareer Investigator Award in FOR (K24 CA97588). The Grant had been titled "Clinical Investigation in Tumor Immunotherapy". A different approach to cancer therapy forms the basis of this proposal. Instead of tumor immunotherapy, the therapy applied is biologically targeted, signal transduction inhibitors administered to melanoma patients. These changes have been taken due to the strengths of this institution (Vanderbilt) and my belief that this approach to cancer therapy has potential for success in patients not presently observed with tumor immunotherapy. In this proposal, the orientation remains clinical translational research and the development of a program to best mentor junior clinical investigators. Melanoma is one of the fastest growing tumor types in the US. For metastatic disease, immunotherapy has been the primary approach to treatment, but has so far not fulfilled its great promise. Therapy targeting (inhibiting) a constitutively activated, signaling pathway critical to the cancer´s growth can provide a remarkable clinical benefit, (i.e. imatinib in CML and GIST, traztuzumab in breast cancer, erlotinib and gefitinib in NSCLC). The success in these malignancies with new therapeutics provides an impetus to search for similarly effective agents in other cancers. In 2002, B-RAF "gain of function" mutations predominantly at V600E were identified in 66% of melanomas tested. Its inhibition with either a kinase inhibitor or RNAi led to tumor regression in animal xenografts . Other mutations cooperate with B-RAF including MITF overexpression, CDK4 or CCND1 amplification, PTEN loss, and activation of the Akt pathway. The identification of prevalent mutations suggest that therapy targeting "gain of function" mutations, overexpressed genes, or activated pathways could provide a major clinical benefit without unacceptable toxicity. The availability of new agents that can target activated pathways important to melanoma is exciting. These drugs will require careful evaluation by well-trained clinical investigators with special attention to what is important to a clinical response. This K24 grant and the melanoma program is vested in training these . translational investigators. Through access to seminars, conferences, tumor boards, a tumor repository, and opportunities in clinical and laboratory training, junior clinical investigators will get excellent training opportunities. The K24 activities will be integrated with the T32, K12 training grants, and the MSCI courses
Keywords: Address; Animals; Attention; Award; base; Belief; cancer therapy; career development; CCND1 gene; CDK4 gene; Clinical; clinical efficacy; Clinical Investigator; Clinical Trials; Development; Dioxygenases; Discipline; Disease; Educational aspects; Erlotinib; Evaluation; Funding; gain of function mutation; Gefitinib; Genes; Grant; Growth; Human; Imatinib; Immunotherapy; Implant; In Vitro; in vivo; indoleamine; inhibitor/antagonist; Institution; kinase inhibitor; Laboratories; Link; malignant breast neoplasm; Malignant Neoplasms; Medical center; melanoma; Mentors; Molecular; Mus; Mutation; Natural immunosuppression; New Agents; NF-kappa B; Non-Small-Cell Lung Carcinoma; novel therapeutics; Nude Mice; overexpression; Pathway interactions; Patients; peer; Pharmaceutical Preparations; pre-clinical; Pre-Clinical Model; programs; PTEN gene; repository; Research; research and development; Research Infrastructure; Research Personnel; Resources; response; RNA Interference; SECTM1 gene; Signal Pathway; Signal Transduction Inhibitor; success; symposium; System; Testing; Therapeutic; therapeutic target; Toxic effect; Training; translational clinical trial; Translational Research; translational study; tumor; Vascular Endothelial Growth Factors; Xenograft procedure
Project start date: 2002-02-15
Project end date: 2013-06-30
Budget start date: 22-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-04-107
5K24CA097588-09 (2011): $173520
TRANSCRIPTIONAL PROGRAMMING OF ASTHMA RELATED PATHOLOGY IN RESPIRATORY EPITHELIA
A Jeffrey, Professor
Children´s Hospital Med Ctr (cincinnati)city: Cincinnati country: United States (us)
Grant 5R01HL095580-03 from National Heart, Lung, And Blood Institute
Abstract: This new application seeks funding to identify and define a transcriptional network that determines Respiratory Epithelial Cell (REC) differentiation, goblet cell hyperplasia, and TH2-like pulmonary phenotypes related to the pathogenesis of asthma and other chronic pulmonary disorders. The application is based on novel data demonstrating the critical roles of a transcriptional network consisting of an Ets family member, SPDEF (SAM pointed domain ets-like factor) and FOXA2 in the regulation of goblet cell differentiation and TH2- like processes in the lung. Our preliminary data demonstrate that differentiation of epithelial cells in conducting airways, is mediated by an intrinsic transcriptional program regulated by FOXA2 and SPDEF that, in turn, drives goblet cell hyperplasia, eosinophilic chemokine, and TH2 cytokine expression from the respiratory epithelium. The application will utilize transgenic mouse models, bioinformatics, in vitro cultures of airway epithelial cells, and biochemistry to determine mechanisms controlling the intrinsic goblet cell program in the lung, and mechanisms by which the respiratory epithelium determines asthma related phenotypes in the mouse lung. Aim 1 will test the hypothesis that the transcription factor FOXA2 plays a critical role in conducting airway epithelial cell differentiation, regulating goblet cell hyperplasia and the expression of genes mediating TH2-like inflammation. Mechanisms by which FOXA2 and FOXA3 differentially regulate gene expression in the respiratory tract will be identified. Aim 2 will test the hypothesis that SPDEF, an ets-like factor, expressed in conducting airways, regulates goblet cell differentiation, in part, via FOXA2. Aim 3 will determine the role of Spdef gene deletion on respiratory epithelial cell differentiation, gene expression, and response to pulmonary allergen and IL-13 challenge, testing the hypothesis that Spdef is required for IL-13/allergen induced goblet cell differentiation. has had a long-standing interest in study of the cellular and molecular biology of the developing alveolar epithelium, and is recently applying these approaches to the study of conducting airway epithelial cell biology. This application is based on the identification of a novel transcriptional network driving goblet cell hyperplasia and TH2-like inflammation from the respiratory epithelium. These studies will provide insights into the pathogenesis of goblet cell hyperplasia and asthma, and will provide basis for the development of new strategies to diagnose and treat chronic respiratory diseases, including asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Goblet cell hyperplasia, inflammation, and tissue remodeling accompany common chronic respiratory disorders, including asthma, CF, and COPD. This application seeks to determine the role of a novel transcriptional network, mediated by FOXA2 and SPDEF, that regulates epithelial cell differentiation in the airways that, in turn, influences inflammation and innate host defense associated with these chronic pulmonary disorders. The work will identify mechanisms regulating airway epithelial homeostasis that will provide novel targets to diagnose and influence the pathogenesis of chronic pulmonary diseases affecting the airways
Keywords: Adult; Affect; age related; airway epithelium; airway remodeling; Allergens; Allergic; Allergic inflammation; alveolar epithelium; Asthma; Automobile Driving; base; Biochemistry; Bioinformatics; bronchial epithelium; Cell Differentiation process; Cellular biology; Characteristics; chemokine; Chronic; Chronic lung disease; Chronic Obstructive Airway Disease; Cystic Fibrosis; cytokine; Data; Development; Diagnosis; Epithelial; Epithelial Cells; Family member; forkhead protein; Funding; Gene Deletion; Gene Expression; Gene Targeting; Genes; Goblet Cells; Health; Histology; Homeostasis; Host Defense; Hyperactive behavior; Hyperplasia; Immune response; In Vitro; in vivo; Inflammation; insight; interest; Interleukin-13; laser capture microdissection; Link; Lung; Lung diseases; Lung Inflammation; Mediating; Messenger RNA; Microarray Analysis; Modeling; Molecular and Cellular Biology; Morbidity - disease rate; Mortality Vital Statistics; mouse model; Mus; novel; Ovalbumin; Pathogenesis; Pathology; Pathway interactions; Phenotype; Physiological; Play; Pneumonia; Process; Production; programs; pulmonary function; Pulmonary Pathology; Regulation; Respiration Disorders; respiratory; Respiratory physiology; Respiratory System; Respiratory tract structure; response; Role; Structure; Structure of respiratory epithelium; Testing; Tissues; trafficking; transcription factor; Transcriptional Activation; Transcriptional Regulation; Transgenic Mice; Work
Relevance: Goblet cell hyperplasia, inflammation, and tissue remodeling accompany common chronic respiratory disorders, including asthma, CF, and COPD. This application seeks to determine the role of a novel transcriptional network, mediated by FOXA2 and SPDEF, that regulates epithelial cell differentiation in the airways that, in turn, influences inflammation and innate host defense associated with these chronic pulmonary disorders. The work will identify mechanisms regulating airway epithelial homeostasis that will provide novel targets to diagnose and influence the pathogenesis of chronic pulmonary diseases affecting the airways
Project start date: 2009-04-01
Project end date: 2013-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-07-070
5R01HL095580-03 (2011): $479645
REAGENTS FOR DETECTION AND ISOLATION OF PULMONARY PROGENITOR CELL POPULATIONS
A Jeffrey, Research Associate Professor
Oregon Health And Science Universitycity: Portland country: United States (us)
Grant 5RC1HL100371-02 from National Heart, Lung, And Blood Institute
Abstract: This application addresses broad Challenge Area (06) Enabling Technologies and specific Challenge Topic, 06-HL-109 Generate Reagents for Studying Lung Cell Biology and Disease Progression. The application focuses on the compelling need to generate cell-surface marker specific reagents useful for identification, study, and isolation of pulmonary stem/progenitor cells. The lung contains a large number of diverse cell types that produce and maintain lung structure and function. Our limited understanding of the complex cellular composition, anatomy, and function of this tissue has slowed the establishment of effective tissue regenerative (repair) and/or cell replacement (transplantation) therapies. We propose to generate and characterize a comprehensive panel of highly useful monoclonal antibodies that will target cell-surface markers on subsets of pulmonary stem and progenitor cell populations. Our approach will be to use currently available model systems of lung repair/regeneration as enriched sources of stem and progenitor cells, to use immunization methods that selectively promote immune responses to cells found in regenerating lung and not in normal lung, and to use tissue- and cell-based antibody screening strategies that allow rapid detection of monoclonal antibodies directed against cell surface molecules. This panel of reagents will be of broad use to the scientific community, and will enable studies of normal lung biology, lung regeneration and repair, the identification of candidate markers for clinical diagnosis of pulmonary disease, and may impact the development of cellular therapies for the treatment of various pulmonary diseases. This application focuses on the compelling need to generate cell-surface marker specific reagents useful for identification, study, and isolation of lung stem/progenitor cells. This panel of reagents will be of broad use to the scientific community, and will enable studies of normal lung biology, lung regeneration and repair, the identification of candidate markers for clinical diagnosis of lung disease, and may impact the development of cellular therapies for the treatment of various lung diseases
Keywords: Ablation; Address; Adult; Anatomy; Antibodies; Area; base; Biological Models; Biology; candidate marker; cell injury; Cell surface; cell type; Cells; Cellular biology; cellular development; clinical Diagnosis; Communities; Complex; Detection; Development; Diagnostic; Diphtheria Toxin; Disease; Disease Progression; Enzymes; Epithelial; Epithelial Cells; Flow Cytometry; Fluorescence-Activated Cell Sorting; Generations; Goals; Immune response; Immunization; Immunofluorescence Microscopy; In Vitro; in vivo; Injury; Kinetics; Liver; Lung; lung development; Lung diseases; Maintenance; Methods; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mortality Vital Statistics; Mus; Natural regeneration; Nature; Normal tissue morphology; novel; Operative Surgical Procedures; Pathogenesis; Pathway interactions; Pneumonectomy; Population; Process; progenitor; public health relevance; rapid detection; Reagent; regenerative; repaired; Research; Research Personnel; respiratory; Respiratory physiology; Respiratory System; Screening procedure; Source; stem; Stem cells; Structure; Technology; Tissue Therapy; Tissues; Transplantation; Validation; Wound Healing
Relevance: This application focuses on the compelling need to generate cell-surface marker specific reagents useful for identification, study, and isolation of lung stem/progenitor cells. This panel of reagents will be of broad use to the scientific community, and will enable studies of normal lung biology, lung regeneration and repair, the identification of candidate markers for clinical diagnosis of lung disease, and may impact the development of cellular therapies for the treatment of various lung diseases
Project start date: 2009-09-30
Project end date: 2011-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
PFA/PA: RFA-OD-09-003
5RC1HL100371-02 (2010): $500000
SPONTANEOUS AUTOIMMUNE MODEL OF PERIPHERAL NEUROPATHY
A Jeffrey, Professor
University Of California San Franciscocity: San Francisco country: United States (us)
Grant 5R01AI050834-10 from National Institute Of Allergy And Infectious Diseases
Abstract: The treatment and cure of autoimmunity remains of paramount importance. The challenges to developing successful therapies are broad, ranging from complex genetics, similarities and differences among target tissues, differential pathogenic mechanisms and an incomplete knowledge of the target antigens. We have shown that the Non-Obese Diabetes (NOD) mouse strain can be used as a mouse model of multiple autoimmune disorders (AID). These other autoimmune diseases were most apparent when regulatory T cells (Tregs) were eliminated and co-stimulatory pathways altered. For instance, NOD mice develop a spontaneous autoimmune disease of the peripheral nervous system, termed Spontaneous Autoimmune Peripheral Polyneuropathy (SAPP), in the absence of CD28 interaction with B7-2. In addition, we observed that in the complete absence of CD28 signals, NOD mice were deficient in Tregs and developed SAPP, sialadenitis, autoimmune thyroiditis and a newly appreciated autoimmune exocrine disease similar to that observed in "fulminant type 1 diabetes" described in Japanese and some Australian patients. Significantly, these various autoimmune diseases could use different pathogenic and co-stimulatory pathways and result from the recognition of distinct as well as potentially overlapping self-antigen specificities. These results have led to the conclusion that the NOD mouse represents a unique model for studying multi-organ autoimmunity. The combination of genetic propensity for autoimmunity and the tools that we have developed in this mouse strain will be exploited to address several key questions. Do unique and/or overlapping antigen specificities distinguish/link these diseases? Are the pathogenic pathways evident for one disease critical for the manifestation of others? Are there common co-stimulation pathways that control the susceptibility and progression of these distinct autoimmune diseases? The following aims are proposed to address these questions Specific Aim #1 To generate tissue antigen-specific effector and regulatory T cell TCR Tg mice based on candidate antigens. Specific Aim #2 To generate tissue antigen-specific effector and regulatory T cell TCR Tg mice using T cell hybridomas and mimotopes. Specific Aim #3 To determine the effector and regulatory pathways and the role of co-stimulation in the distinct autoimmune diseases in NOD mice. Specific Aim #4 To develop green fluorescence protein (GFP)-specific systems to study autoimmunity in NOD mice. Together, the results of these studies will test the hypothesis that the phenotypic manifestation of multi- organ autoimmune diseases is regulated by a coalescence of common and tissue-specific pathways. Moreover these common and distinct pathways are critical for understanding of the immunopathology of these different autoimmune diseases and development of novel therapies
Keywords: Address; Animals; Antigen Targeting; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune thyroiditis; Autoimmunity; autoreactive T cell; Axon; base; CD28 gene; CD80 gene; Cells; Characteristics; Complex; Critical Pathways; cytokine; cytotoxicity; Development; Diabetes Mellitus; Disease; Exocrine pancreas; Fluorescence; Genetic; Goals; Grant; Hybridomas; Image; immunopathology; Immunotherapy; In Vitro; in vivo; Individual; Inflammatory; Insulin-Dependent Diabetes Mellitus; islet; Japanese Population; Knowledge; Lead; Lesion; Link; Modeling; Molecular; mouse model; Mouse Protein; Mouse Strains; Mus; Neuropathy; Non obese; novel; Organ; Pathogenicity; Pathway interactions; Patients; peptide A; Peripheral; Peripheral Nervous System; Peripheral Nervous System Diseases; Phenotype; Polyneuropathy; Predisposition; Production; Promotor (Genetics); Proteins; Reagent; Regulation; Regulatory Pathway; Regulatory T-Lymphocyte; relating to nervous system; Reporter; Research Personnel; Role; Schwann Cells; Screening procedure; Sialadenitis; Signal Transduction; Specificity; Study models; System; T-Cell Receptor; T-Lymphocyte; Testing; Thyroiditis; Tissues; tool; Transgenic Mice; Transgenic Organisms
Project start date: 2001-12-15
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
5R01AI050834-10 (2011): $334234
TRANSCRIPTIONAL CONTROL OF SUBMUCOSAL GLAND FORMATION AND FUNCTION
A Jeffrey, Professor
Children´s Hospital Medical Center Cincicity: Cincinnati country: United States (us)
Grant 1R01HL108907-01 from National Heart, Lung, And Blood Institute
Abstract: The respiratory tract is constantly exposed to microbial pathogens and particles, but is protected by a multitiered host defense system that serves to maintain lung function and sterility. Severe defects in mucociliary clearance, mucus production, and host defense accompany common chronic lung diseases, including cystic fibrosis (CF), chronic obstructive pulmonary disease, and asthma. These disorders are complicated by mucus metaplasia, mucus hyperproduction or inspissation, inflammation, and susceptibility to pulmonary infection. This application seeks to determine the molecular mechanisms underlying deficits in mucociliary clearance associated with pulmonary disease in CF. The work is based on preliminary data demonstrating 1) a novel network of transcription factors that determines both the patterning and differentiation of airway epithelial cells (AECs) lining the developing trachea and bronchi, and the formation of submucosal glands (SMGs) that secrete the majority of fluids, electrolytes, and host defense proteins onto the airway surface and 2) that patterning, growth, diferentiation, and gene expression of AECs and SMGs are influenced by the lack of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). This application will test the hypothesis that PAX9 and an associated transcriptional network play a critical role in the regulation of AEC and SMG morphogenesis and function in the developing and mature airway. This proposal will utilize transgenic mice in which PAX9 and genes associated with PAX9 are conditionally deleted or added to the developing and mature airway epithelium in vivo and in vitro. The molecular and cellular mechanisms by which PAX9 and associated proteins regulate genes and processes critical for AEC and SMG formation and function wil be assessed. The role of the proposed PAX9-dependent regulatory program in the pathogenesis of the pulmonary complications of CF will be determined in CFTR-deficient pigs and mice. This proposal seeks to determine the cellular and molecular basis underlying AEC and SMG morphogenesis and function relevant to the pathogenesis of recurrent infections caused by defects in mucociliary clearance. Throughout life, the lung is exposed to particles, bacteria, viruses, and other microbial pathogens and toxicants that must be removed from the lung by a mucociliary "escalator." Common, chronic lung diseases, including asthma, chronic obstructive lung disease, and cystic fibrosis (CF) are complicated by mucus hyperproduction and recurrent lung infections, leading to long-term disability and mortality affecting millions of individuals world- wide. This application will identify the mechanisms regulating submucosal gland differentiation and function leading to abnormal airway mucociliary clearance and infection. The grant will identify the processes controlling gene expression that are associated with abnormal submucosal gland formation and function in CF and that are also relevant to the pathogenesis of chronic lung diseases in general. Understanding the processes controlling airway epithelial and submucosal gland function provides a framework for the development of new therapies for chronic lung diseases
Keywords: Affect; airway epithelium; Area; Asthma; Bacteria; base; Biology; Bronchi; Bronchiectasis; Cell Differentiation process; cell growth; Cell Line; Chronic lung disease; Chronic Obstructive Airway Disease; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Defect; Development; disability; Disease; Electrolytes; Embryo; Epithelial; Epithelial Cells; Escalator; Family suidae; Gene Expression; Genes; Gland; Grant; Growth; Health; Host Defense; Human; In Vitro; in vivo; Individual; Infection; Inflammation; Life; Liquid substance; Lung; Lung diseases; Metaplasia; microbial; millimeter; Molecular; Morphogenesis; Mortality Vital Statistics; Mucociliary Clearance; Mucous body substance; Mus; Mutation; neglect; NKX2H gene; novel; particle; pathogen; Pathogenesis; Pattern; Perinatal; Play; Predisposition; Process; Processed Genes; Production; progenitor; programs; Promotor (Genetics); Proteins; Pulmonary Cystic Fibrosis; Recurrence; Regulation; Regulatory Pathway; Research; Respiration Disorders; respiratory; Respiratory physiology; Respiratory System; Respiratory tract structure; Role; SCID Mice; Site; Sterility; Structure; Surface; System; Testing; toxicant; Trachea; transcription factor; Transcriptional Regulation; Transgenic Mice; Virus; Work
Relevance: Throughout life, the lung is exposed to particles, bacteria, viruses, and other microbial pathogens and toxicants that must be removed from the lung by a mucociliary "escalator." Common, chronic lung diseases, including asthma, chronic obstructive lung disease, and cystic fibrosis (CF) are complicated by mucus hyperproduction and recurrent lung infections, leading to long-term disability and mortality affecting millions of individuals world- wide. This application will identify the mechanisms regulating submucosal gland differentiation and function leading to abnormal airway mucociliary clearance and infection. The grant will identify the processes controlling gene expression that are associated with abnormal submucosal gland formation and function in CF and that are also relevant to the pathogenesis of chronic lung diseases in general. Understanding the processes controlling airway epithelial and submucosal gland function provides a framework for the development of new therapies for chronic lung diseases
Project start date: 2011-07-01
Project end date: 2015-04-30
Budget start date: 1-JUL-2011
Budget end date: 30-APR-2012
PFA/PA: PA-10-067
1R01HL108907-01 (2011): $393153
OREGON ROYBAL CENTER FOR TRANSLATIONAL RESEARCH ON AGING
A Jeffrey, Professor
Oregon Health And Science Universitycity: Portland country: United States (us)
Grant 5P30AG024978-08 from National Institute On Aging
Abstract: The Oregon Roybal Center for Aging and Technology (ORCATECH) is dedicated to 1) Supporting a unique infrastructure that facilitates the process of developing and translating basic social, behavioral and biological knowledge about aging independently using state of the art technology and engineering; 2) Advancing the use-inspired ORCATECH Living Laboratory model for technology-based health monitoring and support of independent aging, utilizing individual residences and communities with advances in ubiquitous computing and including new constituencies focusing on underserved populations; 3) Accelerating the process of development, translation and dissemination of knowledge gained in the living laboratory through innovative public-private partnerships, cross-disciplinary collaborations and recruitment of new talent into the field. The Center will foster and stimulate translational innovation though a number of mechanisms including its multidisciplinary, multi-institutional Council composed of academic, community and industry leaders, building new national and international research collaborations, establishing a network of retired industry based engineers and health providers for participatory design development (pilot 6-2, ETHICS project) and an internship program for academic trainees to be resident in industry research groups. The Center advances a Living Laboratory model consisting of a network of residences including rural residents, residents living in Section 8, low-income housing (pilot 7-2), and a unique senior community prospectively designed for unobtrusive monitoring of activity with leading-edge technology (pilot 6-1; 7-1). A pilot grant program provides a further mechanism for generating needed new knowledge, recruiting new investigators into the field and enabling future, more definitive studies to be conducted. Initial pilots will address a breadth of key topics including identifying a retired engineer´s cohort to assess health-related technology use attitudes from the unique perspective of technically sophisticated seniors, using in-home technologies to detect dynamic changes in social interactions and engagement during changes of senior´s residences and understanding and enabling an underserved population´s use of home-based technology for independent living
Relevance: ORCATECH is dedicated to developing technologies that optimize health and quality of life for our aging population, particularly those that address two key reasons for loss of independence: loss of mobility and decline in cognitive function. Such technologies hold tremendous promise as public health systems strive to identify innovative and effective ways to better care for our rapidly aging of the population
Project start date: 2004-09-30
Project end date: 2014-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: RFA-AG-09-008
5P30AG024978-08 (2011): $343415
OREGON ALZHEIMER´S DISEASE CENTER
A Jeffrey, Professor
Oregon Health And Science Universitycity: Portland country: United States (us)
Grant 5P30AG008017-22 from National Institute On Aging
Abstract: The Oregon Alzheimer´s Disease Center´s (OADC) goal is to facilitate and advance research on Alzheimer´s disease (AD) and related topics, concentrating our efforts to better define normal aging, the transitions to mild cognitive impairment (MCI) and early dementia. This is achieved by maintaining six Core facilities in association with expert Core personnel to support current research strengths and to be responsive to new knowledge and discoveries in the field. The OADC is coordinated by the Administrative Core to be an efficient unit, working in concert with the research community to facilitate investigation in several major thematic areas such as studies of presymptomatic AD in the very elderly, biomarkers and the genetics of healthy brain aging, home-based technologies for real-time data capture and novel treatment regimens. The Clinical Core provides well-characterized, longitudinally followed research subjects of several kinds 1) early AD and related dementias; 2) non-cognitively impaired or MCI elderly at high risk for dementia, emphasizing the oldest old; and 3) subjects reflecting social and racial diversity (African American and isolated rural populations). The Neuropathology Core is organized to maximize standardized diagnosis, availability of normative and MCI tissue, provision of state of the art protein marker biochemistry and research collaboration through the Pacific Northwest Dementia and Aging (PANDA) Neuropathology Group, a cooperative effort of the OADC and University of Washington ADC Neuropathology Cores. The Biomarkers and Genetics Core responds to the needs of this research using its bank of plasma, CSF and DNA for sophisticated characterization of research subjects toward developing markers of early AD. The Genetics Core also uniquely informs this research by sharing its biomarker and genomic resource widely with others interested in healthy brain aging. The Data Management and Statistics Core links all units with an efficient relational database creating a seamless path to ongoing and future collaborations with the National Alzheimer´s Coordinating Center and other ADCs. The Data Core also provides important assistance and advice in design and statistical analysis to investigators. New information and knowledge of the field is disseminated through the Education and Information Core. This Core uses a variety of educational forums for information dissemination including small seminars, the Internet, and a large public symposium. The Core´s professional education programs emphasize empowering front-line clinicians to meet the challenge of insuring optimal brain aging for our senior population
Project start date: 1997-01-01
Project end date: 2015-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: RFA-AG-10-001
5P30AG008017-22 (2011): $1165812
SOLUBLE NEUREGULINS IN NEUROMUSCULAR AND PERIPHERAL NERVE DEVELOPMENT
A Jeffrey, Associate Professor
Wayne State Universitycity: Detroit country: United States (us)
Grant 5R01NS059947-02 from National Institute Of Neurological Disorders And Stroke
Abstract: The neuregulins (NRGs) are a family of neuronally-derived growth and differentiation factors that ´target" the axoglial interface and neuromuscular junctions (NMJs) through both soluble, heparin-binding and membrane anchored alternatively spliced forms. They promote proliferation, migration, survival, and myelination of both peripheral and central glia. At the NMJ, their role is less clear, but heparin-binding forms accumulate within the basal lamina of NMJs at distinct developmental stages and induce acetylcholine receptors, suggesting that they promote synaptic strength. Given the close proximity of the axon to both muscle and Schwann cell targets, the direct and indirect effects of NRG1 on muscle and nerve have been difficult to establish. Our laboratory focuses on the soluble, heparin-binding forms of NRG1. We found that soluble forms of NRG1 are rapidly released from both sensory and motor neuron axons in response to Schwann cell and muscle-derived neurotrophic factors such as BDNF and GDNF, and that this pathway is regulated by protein kinase C. Once released, NRG1 becomes concentrated within the nerve and at NMJs through highly specific interactions with heparan sulfate proteoglycans (HSPGs). Here, we will explore how NRG1 promotes peripheral nerve and NMJ development in both chick and mouse embryos through two sequential mechanisms. (1) Regulated release from axons by Schwann cell and muscle-derived neurotrophic factors, (2) Neurotrophic factor-induced PKC signaling. Once released from axons, NRG1 will be localized to sites where it accumulates in the extracellular matrix through developmentally-expressed heparan-sulfate proteoglycans (HSPGs). In an important part of these studies, we will also test a novel therapeutic method to target biological therapeutics to axoglial and neuromuscular junctions using NRG1´s heparin-binding domain as a specific targeting motif. Relevance To date there are few effective treatments for diseases of the peripheral and central nervous systems. A promising means to overcome this is to develop biologically-driven therapeutics that use growth factors required for nervous system formation. This proposal will attempt to overcome some off the major limitations in developing such therapeutics through an improved understanding of normal development and improved ways to target novel therapeutics within the nervous system. Understanding the mechanisms that regulate the release and localization of neuregulin at the peripheral nerve and neuromuscular junction will be critical to design effective therapeutics for diseases of peripheral nerve and neuromuscular disorders, such as neuropathy andALS,aswellasCNSdisorders,suchasmultiplesclerosisandschizophrenia.Treatmentscould consist of promoting neuregulin or neurotrophin signaling, and/or promoting neuregulin release through activation of PKC-4 signaling. Our studies also test a more general ´targeting´ system we invented that effectively delivers therapeutics to specific cell types through their unique heparan sulfate composition
Keywords: Affect; Afferent Neurons; ARIA; Axon; Basal lamina; BDNF; Binding; Binding (Molecular Function); Biological; biological signal transduction; Brain-Derived Neurotrophic Factor; Calcium Phospholipid-Dependent Protein Kinase; Calcium-Activated Phospholipid-Dependent Kinase; Cell Communication; Cell Communication and Signaling; Cell Growth in Number; Cell Interaction; Cell Multiplication; Cell Proliferation; Cell Signaling; Cell Survival; cell type; Cell Viability; Cell-Extracellular Matrix; Cell-to-Cell Interaction; Cells; Cellular Proliferation; Central Nervous System; Central Nervous System Diseases; Central Nervous System Disorders; Chick Embryo; Cholinergic Receptors; Cholinoceptive Sites; Cholinoceptors; CNS Diseases; CNS disorder; Communication; dementia praecox; design; designing; Development; Developmental Process; Differentiation and Growth; Disease; disease/disorder; Disorder; ECM; effective therapy; Electroporation; Embryo; Embryonic; Extracellular Matrix; Family; Feedback; GDNF; GDNF gene; GFAC; GGF; GGF2; Glia; Glial Cells; Growth Agents; Growth Factor; Growth Factors, Proteins; Growth Substances; Heparan Sulfate; Heparan Sulfate Proteoglycan; Heparin Binding; Heparitin Sulfate; Heregulin Gene; HGL; HRGA; HSPG; improved; In Vitro; in vivo; insular sclerosis; Intracellular Communication and Signaling; Isoforms; knock-down; Kolliker`s reticulum; L-Serine; Laboratories; loss of function; Mammals, Mice; Measures; Mediating; Membrane; membrane structure; Methods; MGC34632; Mice; migration; Modeling; Molecular Interaction; motoneuron; Motor; Motor Cell; Motor Neurons; MS (Multiple Sclerosis); Multiple Sclerosis; Murine; Mus; Muscle; Muscle Cells; Muscle Cells, Mature; Muscle Tissue; myelination; Myocytes; myoneural disorder; Myoneural Junction; NDF; Nerve; Nerve Cells; nerve cement; Nerve Unit; Nervous; Nervous System; Nervous system structure; Nervous System, CNS; NEU Differentiation Factor Gene; Neu-Differentiation Factor; Neural Cell; Neuraxis; Neuregulins; Neurilemma Cell; Neurilemmal Cell; Neurocyte; Neuroglia; Neuroglial Cells; Neurologic Body System; Neurologic Organ System; neuromuscular; Neuromuscular Diseases; neuromuscular disorder; Neuromuscular Junction; neuronal; Neurons; Neurons, Afferent; Neurons, Sensory; neuropathic; Neuropathy; neurotrophic factor; neurotrophin; neutrophin; new therapeutic target; new therapeutics; next generation therapeutics; Non-neuronal cell; novel; novel therapeutics; NRG Proteins; NRG1; NRG1 gene; NRVS-SYS; pathway; Pathway interactions; Peripheral; Peripheral Nerve Diseases; Peripheral Nerves; Peripheral Nervous System Diseases; Peripheral Nervous System Disorders; Peripheral Neuropathy; Phospholipid-Sensitive Calcium-Dependent Protein Kinase; Phosphorylation; PKC; PNS Diseases; Postsynaptic Membrane; Principal Investigator; programs; Programs (PT); Programs [Publication Type]; Protein Isoforms; Protein Kinase C; Protein Phosphorylation; Proteoheparan Sulfate; public health relevance; Receptors, Acetylcholine; Receptors, ACh; response; RNA Splicing; RNA, Small Interfering; Role; Schizophrenia; schizophrenic; Schizophrenic Disorders; Schwann Cells; Sclerosis, Disseminated; Sensory Cell Afferent Neuron; Sensory-and-motor-derived factor; Serine; Signal Transduction; Signal Transduction Systems; Signaling; siRNA; Site; Small Interfering RNA; SMDF; social role; Spatial Distribution; Splicing; Staging; Synapses; Synaptic; System; System, LOINC Axis 4; Testing; Therapeutic; Therapeutic Uses; Work
Relevance: Relevance: Understanding the mechanisms that regulate the release and localization of neuregulin at the peripheral nerve and neuromuscular junction will be critical to design effective therapeutics for diseases of peripheral nerve and neuromuscular disorders, such as neuropathy andALS,aswellasCNSdisorders,suchasmultiplesclerosisandschizophrenia.Treatmentscould consist of promoting neuregulin or neurotrophin signaling, and/or promoting neuregulin release through activation of PKC-¿ signaling. Our studies also test a more general ´targeting´ system we invented that effectively delivers therapeutics to specific cell types through their unique heparan sulfate composition
Project start date: 2010-02-15
Project end date: 2014-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-07-070
5R01NS059947-02 (2011): $299250
Sponsored Links Excellgen http://Excellgen.com
CELL IMAGING AND ANALYSIS FACILITY CORE
A Jeffrey, Associate Professor
Oregon State Universitycity: Corvallis country: United States (us)
Abstract: The mission of the Cell Imaging and Analysis Facility Core is to provide access to state-of-the-art instrumentation and expertise in confocal microscopy, flow cytometry, cell sorting, and histopathology. Rationale Imaging is an indispensable mode of inquiry for researchers studying the mechanisms by which environmental toxins affect tissues, cells, and subcellular organelles. Recent advances such as fluorescent probes, green fluorescent protein (GFP), confocal optics, two-photon optics, and photoelectronic detectors have improved our ability to image complex tissues. They have enabled us to visualize single molecules and to monitor molecular interactions in live cells. Cost and complexity issues make it impractical for individual investigators to obtain state-of-the-art imaging technologies. Therefore, the need exists for an organized group of specialists with expertise in imaging technologies to acquire the instrumentation, master the applications, and help individual investigators apply the technology to answer specific research questions. Services We support EHSC Investigators to accomplish these tasks ¿ Determine the damage resulting from exposure to environmental toxins and other treatments by providing expert pathological analysis from an experienced Veterinary Pathologist. ¿ Acquire high-resolution images of zebrafish and other models by providing instrumentation, analysis software, infrastructure, and technical assistance. ¿ Quantify the activation state of signal transduction pathways by developing advanced methodology using flow cytometry, microscopy, and mass spectrometry. ¿ Isolate specific cell populations from cell culture, blood, and tissue by providing instrumentation and technical assistance
Keywords: Affect; Binding (Molecular Function); Blood; Cell Culture Techniques; Cell Separation; Cells; cellular imaging; Complex; Computer software; Confocal Microscopy; Core Facility; cost; detector; experience; Exposure to; Flow Cytometry; Fluorescent Probes; Green Fluorescent Proteins; Histopathology; Image; Image Analysis; Imaging technology; improved; Individual; instrumentation; Life; Longevity; Mass Spectrum Analysis; Methodology; Microscopy; Mission; Modeling; Monitor; Optics; Organelles; Pathologist; Population; Predisposition; Research; Research Infrastructure; Research Personnel; Resolution; Services; Signal Transduction Pathway; single molecule; Specialist; Stress; Technology; Tissues; Toxic Environmental Substances; two-photon; Zebrafish
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5P30ES000210-43_5189 (2011): $120834
METABOLIC TARGETS IN PTEN-TUMORS
A Jeffrey
Sanford-burnham Medical Research Institcity: La Jolla country: United States (us)
Abstract: The long-term objective of this study is to identify biochemical pathways that can be used to diagnose and treat human cancers. This study will focus on central carbon metabolism, a process including the uptake and usage of glucose for energy production, cellular biosynthesis, and cell reproduction. Specifically, the work will center on cells in which the tumor suppresser PTEN is inactivated. Since PTEN is frequently inactivated in cancers, including those of the breast, prostate, ovary, endometrium and skin, the work will be relevant to a wide range of human cancers. The study seeks to test the hypothesis that inactivation of PTEN is associated with significant changes in central metabolism, and that some of these metabolic pathways may be exploited as therapeutic and prognostic targets in human cancers. Our preliminary results point to PTEN-dependent changes in metabolic flux in melanoma cells. To test this hypothesis the Specific Aims are to address the following questions using melanoma cell systems as a model 1) What are the differences in central carbon metabolism in PTEN* and PTEN inactive tumors? 2) What metabolic pathways can be exploited as drug targets in PTEN inactive melanomas? 3) What are the effects of drugs on central metabolism in PTEN* and PTEN inactive melanoma cells? 4) Can we identify subsets of PTEN inactive tumors that are highly responsive to a metabolic blockade? The prinriary approach for the study is an analysis of carbon flux through central metabolism using 2D HSQC NMR. Flux through glycolysis, the pentose phosphate pathway, the TCA cycle, and fatty acid biosynthesis, will be quantified and compared under a number of conditions that are known to alter the function of the PTEN pathway. The studies will also define the concentrations of more then twenty key metabolites. Altogether the information gained form this work should provide an understanding how the mechanistic connections occur between PTEN/PI3K/Akt and central metabolism. It is anticipated that the work will also reveal new diagnostic and therapeutic targets
Keywords: Address; Anabolism; anticancer research; Area; Attention; base; Biochemical Pathway; Biological Models; Breast; Breast Cancer Model; Carbon; Cell Death; Cell model; Cell Proliferation; Cells; Citric Acid Cycle; Clinical; comparative; Data; design; Diagnosis; Drug Delivery Systems; Effectiveness; Endometrium; Enzymes; fatty acid biosynthesis; Genes; Glucose; Glycolysis; Goals; Growth; Human; human FRAP1 protein; Hypoxia; imaging modality; in vivo; Individual; insight; knock-down; Lentivirus Vector; Link; Literature; Malignant Neoplasms; Maps; Measures; melanoma; Melanoma Cell; Metabolic; Metabolic Marker; Metabolic Pathway; Metabolism; metabolomics; Modeling; Monitor; Mutate; Mutation; neoplastic cell; new therapeutic target; Non-Essential Amino Acid; Normal Cell; novel diagnostics; Oncogenic; Outcome; outcome forecast; Ovary; Pathway interactions; Patients; Pentosephosphate Pathway; Pharmaceutical Preparations; PIK3CG gene; Process; Production; prognostic; programs; Prostate; PTEN gene; Radial; Reproduction; response; Sampling; Skin; small hairpin RNA; Small Interfering RNA; Staging; System; Testing; Therapeutic; Tissue Microarray; tumor; uptake; Work
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5P01CA128814-03_5058 (2011): $613644
IMMUNOMODULATION OF TRANSPLANT REJECTION BY ANTI-CD3 MAB
A Jeffrey, Professor
University Of California San Franciscocity: San Francisco country: United States (us)
Grant 2R01AI046643-12A1 from National Institute Of Allergy And Infectious Diseases
Abstract: The identification of over 80 autoimmune diseases in humans has led to the realization that a breakdown in self-tolerance accounts for many of the most devastating chronic diseases affecting human health worldwide. Over the past 10 years, it has become apparent that this breakdown in self-tolerance is in large part due to a loss of immune regulation, most prominently a consequence of defective regulatory T cells (Treg) and their inability to control pathogenic immunity. This conclusion has been reached based on numerous studies in animal models of autoimmunity, direct evidence in humans and genetic studies highlight the critical role of this T cell subset. These master regulators of immunity arise both in the thymus (called natural Tregs, nTregs) and in the peripheral immune system (called adaptive Tregs, aTregs) as a consequence of exposure to self-antigens. A loss of Tregs results in a fatal autoimmune disease (termed IPEX in humans), and small changes in Treg numbers or function accompany the onset of autoimmune diseases. In fact, recent data suggest that these regulatory T cells may be altered during disease progression and, in some cases, become so unstable such that they may themselves participate in destructive autoimmunity. Data from patients with a variety of autoimmune diseases has increasingly suggested that Tregs are defective. Several of the susceptibility genes identified in genome studies have shown that several genes that increase the risk for autoimmunity encode variant proteins that control Treg develop and function. However, the basis for these Treg defects and the relative contributions of nTregs versus aTregs in autoimmunity remain controversial. We hypothesize that nTregs are intimately involved in overall immune homeostasis, while aTregs that develop as a consequence of inflammation are critical for controlling local immunity and as such are most susceptible for destabilization. Recent studies in our group using gene expression arrays has identified a unique signature that distinguishes nTregs from aTregs, thus enabling, perhaps for the first time, an ability to distinguish and study these subsets. The goal of this application is to test this hypothesis in mouse models of experimental autoimmune encephalomyelitis, to define the relative importance and functional stability of Tregs in different phases of disease and to determine the relative effectiveness of nTreg versus aTregs in controlling disease activity. To test this hypothesis, we propose the following specific aims 1. To characterize specific attributes and contributions of nTregs and aTregs in protection from autoimmune disease; and 2. To examine the stability of Tregs during autoimmune disease pathogenesis. We anticipate that the results of these studies will enable a more robust understanding of Treg function in humans with autoimmunity, provide new tools for tracking Treg function during disease progression and facilitate our ability to exploit Tregs for therapeutic usage. The identification of 80+ autoimmune diseases in humans has led to the realization that a breakdown in self-tolerance accounts for many of the most devastating chronic diseases affecting human health. This breakdown is in large part do to a loss of immune regulation as a consequence of defective regulatory T cells (Tregs) and their inability to control pathogenic immunity. This project will pursue efforts to define the properties of adaptive versus natural Tregs, their stabilty and ability to control autoimmunity
Keywords: Accounting; Active Immunization; Activities of Daily Living; Adoptive Transfer; Affect; Animal Model; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; base; Biology; CD3 Antigens; Cells; Chronic Disease; CNS autoimmunity; cytokine; Data; Defect; Development; Disease; Disease Progression; disorder control; Effectiveness; Evaluation; Experimental Autoimmune Encephalomyelitis; Exposure to; Foundations; Gene Expression; Gene Proteins; Generations; Genes; Genome; Goals; Graft Rejection; Health; Homeostasis; Human; Human Genetics; Immune; Immune system; Immunity; immunoregulation; Immunotherapy; In Vitro; in vivo; Inbred Mouse; Inflammation; Inflammatory; Inflammatory Response; insight; Light; Modeling; Molecular Profiling; mouse model; Mouse Strains; Mus; novel; Pathogenesis; Patients; Peripheral; Phase; prevent; Property; Protein Fingerprints; Proteins; Regulation; Regulatory T-Lymphocyte; Relative (related person); Reporter; Risk; Role; Self Tolerance; Susceptibility Gene; T-Cell Receptor; T-Lymphocyte Subsets; Testing; Therapeutic; Thymus Gland; Time; tool; Transgenic Mice; Variant
Relevance: The identification of 80+ autoimmune diseases in humans has led to the realization that a breakdown in self-tolerance accounts for many of the most devastating chronic diseases affecting human health. This breakdown is in large part do to a loss of immune regulation as a consequence of defective regulatory T cells (Tregs) and their inability to control pathogenic immunity. This project will pursue efforts to define the properties of adaptive versus natural Tregs, their stabilty and ability to control autoimmunity
Project start date: 2000-03-01
Project end date: 2016-05-31
Budget start date: 10-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-10-067
2R01AI046643-12A1 (2011): $347625
PULMONARY AND CARDIOVASCULAR DEVELOPMENT TRAINING GRANT
A Jeffrey, Professor
Children´s Hospital Medical Center Cincicity: Cincinnati country: United States (us)
Grant 5T32HL007752-18 from National Heart, Lung, And Blood Institute
Abstract: The goal of this Training Grant in Pulmonary and Cardiovascular Biology is to establish a training program for t the enhancement of basic research training in critical aspects of mammalian embryonic and perinatal biology I by providing stipends for three postdoctoral associates and for three predoctoral candidates within the ! University of Cincinnati Graduate Programs. The program draws heavily upon integrated, innovative, andl established Graduate Programs for the study of molecular, developmental, and cell biology and benefits from related programs supported by the NHLBI. This program identifies and recruits promising young doctoral and postdoctoral candidates who will complete their doctoral degree, or a postdoctoral training program. Special attention will be given to recruitment of minorities and to M.D. candidates for this program. Postdoctoral trainees will have the M.D. or Ph.D. degree, or both, and will be selected on a competitive basis. Scientific guidance, career development and course work will be obtained within the graduate programs at the University of Cincinnati College of Medicine in which the training faculty participate. The program has brought together 25 distinguished and well-established investigators with experience using contemporary molecular and cellular strategies to study the developmental biology of tung, heart and blood at Cincinnati Children´s Research Foundation and at the University of Cincinnati College of Medicine. These faculty share research interests and have a long history of collaboration in developmental science. The major themes include study of gene expression during mammalian embryogenesis, gene targeting, and the use of transgenic mice to study gene function and regulation with the developing mouse. The grant will include an administrative core consisting of the Principal Investigator, Executive Committee, external and internal Advisory Boards. Ongoing studies will include a course focused to ethical issues in the conduct of science. Predoctoral trainees will obtain their Ph.D. degrees in the Developmental Biology Graduate Program, Biomedical Sciences Degree Program, Department of Anatomy and Cell Biology, or Department of Molecular Genetics, Biochemistry and Microbiology, at the University of Cincinnati College of Medicine. Regular research meetings and several pertinent seminar series further enhance the program. Progress of each trainee will be reviewed annually by the Executive Committee
Keywords: Cardiovascular system; Development; Grant; Lung; Training
Project start date: 1994-07-15
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5T32HL007752-18 (2011): $273089
TRANSCRIPTIONAL REPRESSION BY POLYCOMB GROUP PRODUCTS
A Jeffrey
University Of Minnesota Twin Citiescity: Minneapolis country: United States (us)
Grant 5R01GM049850-15 from National Institute Of General Medical Sciences
Abstract: The goal of this research is to understand chromatin mechanisms that maintain gene expression states during development. Molecular, genetic and biochemical methods will be used to study the Polycomb group (PcG) transcriptional repressors of Drosophila, which provide one of the premier models for deciphering chromatin mechanisms in development. PcG proteins control selective expression of homeotic (Hox) genes along the anterior-posterior (A-P) axis which, in turn, program differentiation of body structures. For normal body patterning to occur, Hox genes must be kept silent in A-P positions where they are not normally expressed. Hox expression patterns are set by segmentation gene products in 2-hour-old fly embryos, but these initial regulators decay by about 4 hours. The Polycomb group proteins then assume control to maintain Hox gene silencing during the rest of development. Thus, PcG proteins provide molecular memory of spatial cues present in early embryos. Current models suggest that PcG silencing is maintained through covalent histone modification and stable association of PcG protein complexes in the local chromatin. The PcG proteins, and the chromatin complexes they form, are highly conserved from flies to humans. Human PcG proteins play critical roles to maintain pluripotency of embryonic stem cells. Overabundance of PcG proteins is also implicated in disease progression in cancers of the breast, prostate, and other tissues. Their expanding importance in stem cell biology and cancer epigenetics underscores the need to understand basic PcG chromatin mechanisms. This project will determine PcG mechanisms using Drosophila, which provides one of the best-characterized systems for in vivo investigation of PcG silencing. This research will investigate molecular roles of PcG complexes and their subunits. Much of the work focuses on a PcG complex called PRC2 (Polycomb repressive complex 2). PRC2 has four core subunits and an enzyme activity that methylates histone H3 on lysine-27. One Aim is to determine how the noncatalytic subunits make key inputs to PRC2 function in vitro and in vivo. A second Aim addresses in vivo consequences of histone methylation and whether PRC2 has any function besides enzyme activity. A third Aim is to define the molecular role of another critical PcG repressor, called Sex comb on midleg (SCM), which appears to work independently of PRC2. The methods will include loss-of-function and over-expression studies, site-directed mutagenesis, transgene manipulation, chromatin immuneprecipitation, enzyme assays, protein purification and chromosome immunostaining. Fulfillment of these Aims should advance knowledge of basic PcG mechanisms and also of epigenetic processes that control human stem cell fates and that underlie certain human cancers. This research is to determine how a set of highly conserved regulatory proteins, called Polycomb group (PcG) proteins, keep genes turned off during animal development. In humans, PcG proteins are critical for embryonic stem cell maintenance and they are implicated in breast cancer, prostate cancer, and cancers of other tissues. This research will advance basic understanding of gene regulatory mechanisms and provide knowledge that could impact stem cell applications in medicine and development of anti-cancer strategies
Keywords: Accounting; Address; Alleles; Animals; Anterior; Binding (Molecular Function); Biochemical; Biological Assay; Body Patterning; Catalytic Domain; Cell Maintenance; Cells; Chromatin; chromatin protein; Chromosomes; cofactor; Complex; Cues; Data; Development; Disease Progression; Drosophila genus; Embryo; embryonic stem cell; enzyme activity; Enzymes; Epigenetic Process; fly; Gene Expression; gene repression; Gene Silencing; Genes; Genetic; genetic regulatory protein; Genomics; Goals; Health; Histone H3; histone methyltransferase; histone modification; Histones; Hour; Human; human embryonic stem cell; human stem cells; In Vitro; in vivo; induced pluripotent stem cell; Investigation; Knowledge; Location; loss of function; Lysine; malignant breast neoplasm; Malignant neoplasm of prostate; Malignant Neoplasms; Mammals; Mediating; Medicine; meetings; Memory; Methods; Methylation; Modeling; Molecular; Molecular Genetics; mutant; novel; Nucleosomes; Pattern; Play; pluripotency; Polycomb; Positioning Attribute; PRC1 Protein; programs; Prostate; protein complex; protein purification; Proteins; public health relevance; Reaction; Recruitment Activity; Regulation; Regulator Genes; Research; Rest; Role; selective expression; Sex Combs on Midleg; Site; Site-Directed Mutagenesis; Sorting - Cell Movement; Staging; stem cell biology; stem cell fate; Stem cells; Structure; Surface; System; Testing; Tissues; Transcription Repressor/Corepressor; Transgenes; Work; Workplace
Relevance: Public Health Relevance This research is to determine how a set of highly conserved regulatory proteins, called Polycomb group (PcG) proteins, keep genes turned off during animal development. In humans, PcG proteins are critical for embryonic stem cell maintenance and they are implicated in breast cancer, prostate cancer, and cancers of other tissues. This research will advance basic understanding of gene regulatory mechanisms and provide knowledge that could impact stem cell applications in medicine and development of anti-cancer strategies
Project start date: 1996-08-01
Project end date: 2013-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-07-070
5R01GM049850-15 (2011): $315724
HEALTHY LIVING PARTNERSHIP TO PREVENT DIABETES (HELP PD) PHASE 3 (FORMERLY TRIP)
A Jeffrey, Chair
Wake Forest University Health Sciencescity: Winston-salem country: United States (us)
Grant 5R18DK069901-06 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: The Diabetes Prevention Program (DPP) demonstrated that weight loss achieved through changes in physical activity and diet was more effective at preventing type 2 diabetes mellitus (DM) than a pharmacologic intervention; however, translation of the DPP into the community has lagged for multiple reasons. The Healthy Living Partnership to Prevent Diabetes (HELP PD) Trial (funded Sept. 2006 - Aug. 2011) is a translational study of 300 overweight or obese persons with pre-diabetes randomized to usual care (UC) or a group-based lifestyle intervention (LI) facilitated by community health workers (CHWs) and supported by staff of a Diabetes Care Center. To date, recruitment, retention, intervention, and assessment have been excellent and 6-month weight loss is averaging 6.4%. Since Aug. 2007, we have enrolled 258 participants, and we plan to enroll 42 more by Mar. 2009. Follow-up was funded for a uniform 2 years; hence, the earliest-enrolled participants (enrolled in Aug. 2007) will complete follow-up for HELP PD in Aug. 2009. The primary goal of this competitive renewal is to test the long-term glucose lowering effects of the HELP PD intervention by randomizing the LI group to continued group maintenance (GM) or self-directed maintenance (SM) and following the UC group for additional comparison purposes. Additional funding, partially overlapping with current funding, is requested to re-enroll participants as they complete initial follow-up, thus giving those who continue GM a seamless intervention and the opportunity to begin new follow-up visits 6 months after the final HELP PD visit for an additional 36-48 months. We will test the value of long-term GM versus an initial 2-year intervention followed by SM, with the added value of a true comparison group (UC) to define biological effects. Secondary outcomes include other biologic parameters (insulin, lipids, blood pressure, weight, waist), behaviors, and cost-effectiveness. We will have good power to evaluate the effectiveness of the HELP PD approach in maintaining glucose and weight change, and other biologic effects. Notably, follow-up in DPP was, on average, 3.2 years. If this application is approved, follow-up will be extended from 24 to 60-72 months for this cohort, and we will be able to transition into extended maintenance without a gap in intervention; hence, we are well positioned to test the proposed hypotheses. Demonstrating the longer term effectiveness of HELP PD represents a key step in establishing the value of this approach to translation of DM prevention into the community. This crucial evidence will be used to support reimbursement policy for DM prevention, dissemination of the HELP PD CHW approach and generalization to other behaviorally influenced chronic diseases. In light of the increasing rates of incidence, prevalence, and overall public health burden, the prevention of diabetes is a critical public health issue. This project is testing the impact of a long-term maintenance approach following an existing diabetes prevention translational study (HELP PD) on measures of diabetes risk. Although preliminary data indicate that HELP PD has been successful at inducing short-term weight loss, the proposed project aims to examine the impact of long-term maintenance of weight loss on diabetes prevention
Keywords: Address; Age; base; Behavior; behavior change; Behavioral; Biological; Blinded; Blood Pressure; Body Weight Changes; Body Weight decreased; cancer prevention; Cardiovascular system; Caring; Characteristics; Chronic Disease; clinical effect; cohort; Communities; Community Developments; Community Health; comparison group; Consent; cost; cost effective; cost effectiveness; Data; design; Development; Diabetes Mellitus; Diabetes prevention; diabetes prevention program; diabetes risk; Diet; Dietary intake; disorder prevention; economic evaluation; effective intervention; Effectiveness; Enrollment; Ethnicity aspects; fasting glucose; follow-up; Funding; Gender; Glucose; Goals; group intervention; HDL-triglyceride; Health; Health Benefit; Health Promotion; health related quality of life; Homeostasis; Hypertension; improved; Incidence; Insulin; Insulin Resistance; Intervention; intervention effect; intervention program; Knowledge; Life; Life Style; lifestyle intervention; Light; Lipids; Maintenance; Masks; Measurement; Measures; Mediating; meetings; Metabolic; Metabolic syndrome; Metabolism; Modeling; Monitor; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Overweight; Participant; Persons; Phase; Physical activity; Policies; Positioning Attribute; Prediabetes syndrome; Prevalence; prevent; Prevention; primary outcome; programs; public health medicine (field); public health relevance; Randomized; Research Personnel; Research Priority; Safety; secondary outcome; Serious Adverse Event; social cognitive theory; Societies; Study Section; success; Testing; Time; Translating; translational approach; translational study; Translations; treatment as usual; Visit; waist circumference; Weight; weight loss intervention; Weights and Measures
Relevance: In light of the increasing rates of incidence, prevalence, and overall public health burden, the prevention of diabetes is a critical public health issue. This project is testing the impact of a long-term maintenance approach following an existing diabetes prevention translational study (HELP PD) on measures of diabetes risk. Although preliminary data indicate that HELP PD has been successful at inducing short-term weight loss, the proposed project aims to examine the impact of long-term maintenance of weight loss on diabetes prevention
Project start date: 2004-12-01
Project end date: 2015-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PAR-06-532
5R18DK069901-06 (2011): $612095
2R18DK069901-05 (2010): $653324
LASER SCANNING CONFOCAL MICROSCOPE
A Jeffrey, Associate Professor
Univ Of Massachusetts Med Sch Worcestercity: Worcester country: United States (us)
Grant 1S10RR027844-01A1 from National Center For Research Resources
Abstract: The Department of Cell Biology Confocal Core serves a large and strong department which ranks in the top ten among all United States medical school cell biology departments for NIH funding. The department has 28 faculty members, 22 research faculty members, and 29 jointly-appointed faculty members, most of whom use confocal imaging. The Core also provides imaging for the Cancer Center, and for other departments that lack their own dedicated confocal imaging capability. The only confocal microscope in the core is more than 11 years old and will not long be supported by the manufacturer. We request funds to replace the existing instrument with a state-of-the-art laser scanning confocal microscope suitable for an imaging core with a large number of users having diverse needs. We have chosen the Leica SP5 AOBS, a laser scanning confocal microscope that will provide maximal technical capability while requiring the least retraining of our large population of existing users. Confocal microscope technology has made major advances in the last decade. We will bring these newer technologies, and the experimental techniques they enable, to our large base of NIH-funded researchers
Keywords: 11 year old; base; Cancer Center; Cellular biology; Faculty; Funding; Image; instrument; Lasers; Manufacturer Name; medical schools; member; Microscope; new technology; Population; Research; Research Personnel; Scanning; Techniques; Technology; United States; United States National Institutes of Health
Project start date: 2011-05-01
Project end date: 2012-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PAR-10-082
1S10RR027844-01A1 (2011): $534652
STRATEGIES FOR REDUCING THE IMPACT OF IMPLICIT STEREOTYPING OF HISPANICS IN RECOM
A Jeffrey
University Of Arizonacity: Tucson country: United States (us)
Grant 1R01MD005902-01A1 from National Institute On Minority Health And Health Disparities
Abstract: The current proposal seeks support for research on the role of implicit or unconscious stereotyping in the unequal treatment of Hispanics who seek healthcare. Research in social psychology on prejudice, stereotyping and discrimination shows that while many biases are conscious and deliberate, the expression of bias is often unintentional because people hold negative attitudes and stereotypes at an implicit or unconscious level. Thus, implicit biases may leak into the way health professionals acquire information, diagnose, and treat Hispanic patients, but the impact of implicit bias can also be mitigated by training health care providers to control their implicit biases, and by empowering Hispanic patients to use strategies that will deactivate the implicit biases held by their health care providers. The proposed research translates basic theory and methodology from the social psychological study of implicit stereotyping to achieve two broad goals for reducing bias against Hispanic patients First, two experiments will examine the degree to which medical and nursing students hold the conscious and unconscious negative stereotype that Hispanic patients do not comply with diagnosis and treatment recommendations. Two experiments will examine how factors like fatigue and cognitive load moderate the implicit activation of the negative stereotype about Hispanic patients, and how the implicit activation of the stereotype mediates the acquisition of information, diagnosis and treatment of a Hispanic patient. Secondly, the research will develop and test new approaches to cultural competency and health literacy that can reduce implicit stereotyping of Hispanic patients. One project will test the effectiveness of a workshop to teach medical and nursing students about the psychology of implicit stereotyping and provide them strategies, like perspective taking, egalitarian goal activation, and collecting counter-stereotypic information that reduce the activation of implicit stereotypes. Another project will test the impact of patient-delivered strategies for inducing perspective taking, priming egalitarian goals, and providing counter-stereotypic information that reduce the activation of implicit stereotypes in a health care provider. The results of these studies will take significant steps toward understanding and reducing the role of unconscious stereotyping in the care provided to Hispanic patients. Involving both health care providers and Hispanic patients in the bias reduction process has the potential to enhance the health care provider´s use of cultural competency and improve the Hispanic patient´s participation in their care. Both of these outcomes, in turn, can improve communication between provider and patient, which will lead to better diagnosis and treatment recommendations for patients, and enhanced health literacy efficacy in Hispanic patients. This R01 award will support research on the role that unconscious stereotyping plays in creating health disparities for Hispanics who seek health care in a border state like Arizona. The award will support six studies over three years to examine how unconscious stereotypes leak into the way health professionals acquire information, diagnose, and treat Hispanic patients, and on how unconscious stereotyping can be reduced by training health care providers to control their implicit biases, and by empowering Hispanic patients to use strategies that deactivate the unconscious stereotypes held by health care providers. ) )
Keywords: AIDS/HIV problem; Arizona; Attitude; Award; Belief; Caring; Centers for Disease Control and Prevention (U.S.); Cognitive; colorectal cancer screening; Communication; Conscious; cultural competence; design; Diabetes Mellitus; Diagnosis; Discrimination (Psychology); disorder prevention; Educational process of instructing; Educational workshop; Effectiveness; empowered; Ethnic group; Exhibits; Fatigue; Goals; Health; health care delivery; health care quality; health disparity; health literacy; Health Personnel; Health Professional; Healthcare; high risk; Hispanics; improved; Incidence; Individual; innovation; Intake; Interview; Lead; Malignant Neoplasms; Mediating; Medical; Medical Students; Methodology; Mexican; minority health; Mortality Vital Statistics; Motivation; novel strategies; Nursing Students; Outcome; Pathway interactions; Patient Noncompliance; Patient Participation; Patients; Phase; Play; Pneumococcal Infections; Prejudice; Process; Provider; psychologic; Psychology; Quality of Care; racial and ethnic; racial and ethnic disparities; Reaction Time; Recommendation; Reliance; Research; research study; Research Support; Risk; Role; Shoulder; skills; Smoker; smoking cessation; social; Social Psychology; Stereotyping; Testing; theories; Training; Translating; Unconscious State; Vaccination; Withholding Treatment
Project start date: 2011-06-01
Project end date: 2014-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: RFA-MD-11-001
1R01MD005902-01A1 (2011): $314928
STREPTOCOCCUS MUTANS STRAIN SUSCEPTIBILITY DIFFERENCES TO HOST DEFENSE PEPTIDES
A Jeffrey, Professor
University Of Iowacity: Iowa City country: United States (us)
Grant 5R21DE019475-02 from National Institute Of Dental & Craniofacial Research
Abstract: The contributions of host defense peptides in innate immunity and the shaping of the commensal flora are just beginning to be defined. Streptococcus mutans is a commensal within dental plaque that can attain cariogenic proportions when host dietary choices include significant amounts of sucrose. However, S. mutans strain variability is considerable at the DNA level and so it is reasonable to expect that strain variability in cariogenic potential also exists, including differing abilities to resist host immune mechanisms. This application proposes to test the hypothesis that S. mutans strains vary in their susceptibility patterns to host defense peptides. As a consequence we believe that the host-specific quantity and distribution of these peptides influences plaque colonization by particular S. mutans strains thereby helping to define overall caries risk. To test the hypothesis two specific aims are proposed. Aim 1 will examine S. mutans clones isolated from plaque samples obtained from caries-active and caries-free children and determine their susceptibility patterns to a panel of oral host defense peptides. Aim 2 will measure naturally occurring levels of host defense peptides in saliva samples corresponding to the saliva samples from Aim 1, and determine the levels of correlation between the distribution and quantity of host defense peptides, the susceptibility profiles of unique S. mutans genotypes, and the caries status of the children. The completion of this study will provide information regarding the potential contribution of host innate immunity, in the form of host defense peptides, to shape S. mutans colonization and therefore caries risk. This information will also be useful in assessing the potential efficacy of host defense peptides as therapeutic anti-caries agents. This project will test the hypothesis that different strains Streptococcus mutans, the primary bacterial cause of dental caries, vary in their susceptibilities to host defense peptides. The hypothesis will be tested by assessing the levels of correlation between the distribution and quantity of host defense peptides, the susceptibility profiles of unique S. mutans genotypes, and the caries status of the children. The results will help determine the extent to which host innate immunity may influence colonization of dental plaque with particular strains of S. mutans and may therefore shape overall caries risk
Keywords: antimicrobial peptide; Characteristics; Child; Coupled; Dental caries; Dental Plaque; Development; Disease; DNA; Ecology; experience; Flowers; Foundations; Genotype; Host Defense; Immune; Individual; Integration Host Factors; Link; Measures; Metabolic; Natural Immunity; Oral; oral pathogen; Pattern; Peptides; Predisposition; Process; public health relevance; Relative (related person); Research; Resistance; Resistance profile; response; Risk; Saliva; Salivary; Sampling; Shapes; Specificity; Streptococcus mutans; Sucrose; Testing; Therapeutic; Virulence
Project start date: 2010-06-15
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-09-164
5R21DE019475-02 (2011): $222750
Sponsored Links Excellgen http://Excellgen.com
THE ACTIVATION OF ERBB3 SIGNALING AS A RESISTANCE MECHANISM TO TARGETED THERAPIES
A Jeffrey, Assistant Professor
Massachusetts General Hospitalcity: Boston country: United States (us)
Grant 5R01CA137008-03 from National Cancer Institute
Abstract: The Center for Transcriptional Consequences of Human Genetic Variation (CTCHGV) will develop innovative and powerful genetic engineering methods and use them to identify genetic variations that causally control gene transcription levels. Genome Wide Association Studies (GWAS) find many variations associated with disease and other phenotypes, but the variations that may actually cause these conditions are hard to identify because nearby variations in the same haplotype blocks consistently co-occur with them in human populations, so that specifically causative ones cannot be distinguished. About 95% of GWAS variations are not in gene coding regions, and many of these presumably associate with altered gene expression levels. CTCHGV will identify the variations that directly control gene expression by engineering precise combinations of changes to gene regulatory regions that break down the haplotype blocks, allowing each variations´ effect on gene expression to be discerned independently of the others. To perform this analysis, CTCHGV will extract ~100kbps gene regulatory regions from human cell samples, create precise variations in them in E. coli, and re-introduce the altered regions back into human cells, using zinc finger nucleases (ZFNs) to efficiently induce recombination. CTCHGV will target 1000 genes for this analysis (Aim 1), and will use human induced Pluripotent Stem cells (iPS) to study the effects of variations in diverse human cell types (Aim 2). To explore the effects of variations in complex human tissues, CTCHGV will develop methods of measuring gene expression at transcriptome-wide levels in many single cells, including in situ in structured tissues (Aim 3). Finally, CTCHGV will develop novel advanced technologies that integrate DNA sequencing and synthesis to construct thousands of large DNA constructs from oligonucleotides, that enable very precise targeting and highly efficient performance of ZFNs, and that enable cells to be sorted on the basis of morphology as well as fluorescence and labeling (Aim 4). CTCHGV will also develop direct oligo-mediated engineering of human cells, and create "marked allele" iPS that will enable easy ascertainment of complete exon distributions for many pairs of gene alleles in many cell types. RELEVANCE CTCHGV methods will yield precise knowledge of effects of human genetic variations on gene expression that will both refine and go beyond GWAS-derived associations between non-coding variations and disease. Powerful new CTCHGV genetic engineering methods will directly enable gene therapy. CTCHGV iPS and single-cell transcriptome technologies will increase understanding of diverse and complex human tissues
Keywords: Adoption; Affect; Alleles; allelic variant; Allelomorphs; American; Americas; Archives; Area; Assay; Award; Back; Bar Codes; base; Bioassay; Biologic Assays; Biological Assay; biological research; biological signal transduction; Biomedical Research; Biotechnology, Genetic Engineering; Body Tissues; Businesses; Cancers; Causality; cDNA; Cell Communication and Signaling; cell engineering; Cell Line; Cell Lines, Strains; Cell Signaling; cell type; CellLine; Cells; cellular engineering; Church; cleaved; Cleaved cell; clinical practice; Closure by Ligation; CNP; Code; Coding System; cohort; Collaborations; Commit; Communities; Complementary DNA; Complex; Copy Number Polymorphism; copy number variation; cultured cell line; Data; Deoxyribonucleic Acid; Development; Development and Research; Disease; disease causation; disease etiology; disease/disorder; disease/disorder etiology; Disorder; disorder etiology; diverse populations; DNA; DNA biosynthesis; DNA Recombination; DNA recombination (naturally occurring); DNA Replication; DNA Sequence; DNA Synthesis; DNA, Complementary; Dorsum; E coli; Effectiveness; Elements; embryonic stem cell; Engineered Gene; EngineeredGene; Engineering; Engineerings; Ensure; ES cell; Escherichia coli; Etiology; Exhibits; Exons; Fluorescence; Functional RNA; Funding; Gametes; Gene Expression; Gene Expression Profile; gene expression signature; Gene Targeting; gene therapy; Gene Transcription; Gene Transfer Clinical; Gene Transfer Procedure; Gene variant; Gene-Tx; General Hospitals; Generations; Genes; Genetic; Genetic Diversity; Genetic Engineering; Genetic Intervention; Genetic Recombination; genetic regulatory element; genetic therapy; Genetic Transcription; Genetic Variation; Genome; genome sequencing; genome wide association scan; genome wide association studies; genome wide association study; genome-wide scan; genomewide association scan; genomewide association studies; genomewide association study; genomewide scan; Genomics; Germ Cells; Germ-Line Cells; Goals; Grant; GWAS; Haplotypes; Health; Hematopoietic; Heterogeneity, Population; heterogeneous population; homologous recombination; Human; Human Engineering; Human Genetics; Human Genome; Human Resources; human tissue; Human, General; Image; imaging; improved; In Situ; Individual; induced pluripotent stem cell; initial cell; innovate; innovation; innovative; insight; Institutes; Intervention, Genetic; Intracellular Communication and Signaling; Isoforms; Knowledge; knowledge base; Label; language translation; Letters; leukemia/lymphoma; Libraries; Life; Ligation; Linkage Disequilibrium; Linkage Disequilibriums; lymphoma/leukemia; Maintenance; Maintenances; malignancy; Malignant Neoplasms; Malignant Tumor; Man (Taxonomy); Man, Modern; Manpower; Massachusetts; Measurement; Measures; Mediating; medical schools; Medicine; meetings; member; Methods; Methods and Techniques; Methods, Other; Mind; Modification; Molecular; Molecular Biology, Gene Therapy; Molecular Biology, Genetic Engineering; Morphology; National Heart, Lung, and Blood Institute; National Institutes of Health; National Institutes of Health (U.S.); neoplasm/cancer; next generation; NIH; Non-Coding; Non-Coding RNA; novel; nuclease; Nucleic Acid Regulatory Sequences; Nucleotides; Oligo; Oligonucleotides; Open Reading Frames; open source; Optics; ORFs; Patients; Pediatric Hospitals; Pediatric Research; Performance; personnel; Phenotype; Physiology; Polymerase; Population; population based; Population Heterogeneity; post-doc; post-doctoral; Postdoc; Postdoctoral Fellow; Principal Investigator; professor; programs; Programs (PT); Programs [Publication Type]; Protein Coding Region; Protein Isoforms; R & D; R&D; Recombinant DNA Technology; Recombination; Recombination, Genetic; Regulator Regions, Nucleic Acid; Regulatory Regions; Regulatory Regions, Nucleic Acid (Genetics); Regulatory Sequences, Nucleic Acid; repository; Reproductive Cells; Research; research and development; Research Associate; Resolution; RNA Expression; RNA Splicing; Sampling; Science of Medicine; Sex Cell; sexual cell; Signal Transduction; Signal Transduction Systems; Signaling; single molecule; Societies; Solid; sorting; Sorting - Cell Movement; Splicing; Stem Cell Development; stem cell of embryonic origin; Structure; success; synthetic biology; Targetings, Gene; Techniques; Technology; Testing; Therapy, DNA; Time; Tissues; trait; Transcript; Transcription; Transcription, Genetic; transcriptome; transcriptomics; Translating; Translatings; United States National Institutes of Health; user-friendly; Variant; Variation; Variation (Genetics); whole genome association studies; whole genome association study; Work; Writing; Zinc Finger Domain; Zinc Finger Motifs; Zinc Fingers
Project start date: 2009-03-01
Project end date: 2013-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-07-070
5R01CA137008-03 (2011): $316803
ANGIOGENEIS AND THE EXTRACELLULAR MATRIX
A Jeffrey, Associate Professor
University Of Utahcity: Salt Lake City country: United States (us)
Grant 5R01HL077683-08 from National Heart, Lung, And Blood Institute
Abstract: The broad objective of this Bioengineering Research Grant is to study biomechanical interactions of angiogenic microvessels with the extracellular matrix (ECM) on the microscale level to develop a computational model of angiogenesis. Our previous work has lead to the hypothesis that the ECM structure adjacent to angiogenic microvessels and the mechanical loading conditions are potential determinants of angiogenic sprouting and neovessel growth and guidance. To test this hypothesis, we will evaluate angiogenesis in a collagen gel-based, 3- dimensional organ culture system of microvessels in the presence of altered mechanical boundary conditions and perturbed collagen fibril structure and gel properties. The interaction dynamics between the angiogenic sprouts and neovessels that form in this culture system with the adjacent collagen matrix and the overall tissue construct behavior will be modeled and analyzed using material point method (MPM). Experimental data of both microvessel behavior and collagen structure dynamics, gathered with advanced imaging techniques, will provide the framework and parameters for the modeling effort. Because of the importance of the local, microscale, interactions between the microvessel and the ECM, the model will emphasize these aspects. In addition to establishing a better understanding of the relationship between angiogenic vessels, the surrounding ECM structure, and the mechanics of the tissue undergoing angiogenesis, the project will provide the basis for improved control of tissue vascularization in both native tissues (e.g., repairing ischemic tissue) and tissue engineered constructs. The proposed research will elucidate fundamental aspects of the roles of mechanical forces and extracellular matrix structure in angiogenesis. The process of angiogenesis is an integral feature of wound healing and tumor metastastis. The results of this research will provide a mechanistic understanding of the interaction of angiogenic microvessels with the extracellular matrix, and provide guidelines for the design and development of vascularized tissue replacements
Keywords: 3-Dimensional; Address; Adhesions; Algorithms; angiogenesis; Architecture; base; Behavior; Binding (Molecular Function); Biomechanics; Biomedical Engineering; Cell surface; Collagen; Collagen Fiber; Collagen Fibril; Computer Simulation; Data; design; Development; Endothelial Cells; Experimental Models; Extracellular Matrix; Extracellular Matrix Degradation; Fluorescence; Funding; Gel; Generations; Growth; Guidelines; Health; Image; imaging modality; Imaging Techniques; improved; In Vitro; in vitro Model; innovation; Lead; Life; Matrix Metalloproteinases; Measurement; Mechanics; Methodology; Methods; Microscope; Microscopy; Modeling; neovascular; NIH Program Announcements; Organ Culture Techniques; Pericytes; Process; Property; repaired; Research; Research Project Grants; Role; Sampling; simulation; Structure; System; Technology; Testing; Time; Tissue Engineering; Tissues; tool; Traction; tumor; Validation; Vascularization; Work; Wound Healing
Project start date: 2004-01-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-279
5R01HL077683-08 (2011): $523999
ADVERSE EFFECTS OF ANTIDEPRESSANTS IN PEDIATRIC NON-OCD ANXIETY DISORDERS
A Jeffrey, Investigator
Research Inst Nationwide Children´s Hospcity: Columbus country: United States (us)
Grant 5R03MH083248-02 from National Institute Of Mental Health
Abstract: The association between antidepressant treatment and suicidal thoughts and behavior in children and adolescents has been the topic of recent debate. Much of our knowledge about treatment emergent risks associated with antidepressant treatment in youth derive from short-term, randomized, controlled trials (RCTS). These trials are limited in detecting adverse effects of medications due to the relatively small number of participants required to test primary efficacy end points. The proposed R03 small grant project will address gaps in knowledge by determining the relative safety and tolerability of antidepressant medications in the acute treatment of childhood anxiety, based on a secondary analysis of individual patient-level data of all available randomized controlled trials (RCTs) comparing antidepressants and placebo for generalized anxiety disorder, separation anxiety disorder, and social phobia. Outcomes will include treatment emergent adverse events (TEAEs) and treatment-induced changes in vital signs, cardiovascular effects, height, weight, and clinical laboratory parameters. The study also aims to identify patient subgroups at highest risk of adverse outcomes during acute treatment. This work will build on the PI´s existing databases of antidepressant RCTs for pediatric depression, OCD, and non-OCD anxiety disorders. Meta-analysis of individual patient data (MAP) has been proposed as the most rigorous empirical method available to determine the relative efficacy and safety of treatments. This study is novel in that MAP allows for statistically powerful time-to-event analysis, identification of subgroups of patients at differential risk of adverse outcomes, and adjustment for variables that may have confounded the original treatment comparisons. We will therefore be able to examine questions of safety and tolerability otherwise unanswerable by a single trial, a multi-center RCT, or a traditional study-level meta- analysis. The feasibility of this project is supported by existing commitments from PIs and industry sponsors to provide our team with the patient-level data necessary to accomplish the goals of this application. These findings will be of benefit to clinicians who manage and treat anxious youth with these medications. This preliminary research will also build the foundation for future work examining the treatment emergent risks and side effects burden of psychotropic medications in other psychiatric disorders, including MDD, OCD, and bipolar disorder
Keywords: 0-11 years old; abuse of substances; Acute; Address; Adolescent; Adolescent Youth; Adverse effects; Adverse event; Adverse Experience; Adverse reactions; Affective Psychosis, Bipolar; Age; Agitation; Antidepressant Agent; Antidepressant Drugs; Antidepressants; Antidepressive Agents; Anxiety; Anxiety Disorders; Award; base; Behavior; behavioral disinhibition; Berlin; bipolar affective disorder; Bipolar Disorder; Boxing; Cardiovascular; Cardiovascular Body System; Cardiovascular system; Cardiovascular system (all sites); Characteristics; Child; Child Youth; Childhood; childhood anxiety; children; Children (0-21); circulatory system; City of Berlin; Clinical; clinical data repository; clinical data warehouse; Clinical Trial Overviews; Controlled Clinical Trials; cost; Cross-Product Ratio; Data; Data Banks; Data Bases; Data Pooling; Data Poolings; data repository; Databank, Electronic; Databanks; Database, Electronic; Databases; depression; Depression and Suicide; depressive; depressive symptoms; design; designing; Disease; disease severity; disease/disorder; Disinhibition; Disorder; drug/agent; Drugs; Emotional Depression; Ethnic Origin; Ethnicity; Ethnicity aspects; Event; Excitement, Psychomotor; Family; fatal attempt; fatal suicide; FDA; Feeling suicidal; Food and Drug Administration; Food and Drug Administration (U.S.); Foundations; Future; Generalized Anxiety Disorder; Goals; Grant; Hearing; hearing perception; heavy metal lead; heavy metal Pb; Height; high risk; History; Human, Child; improved; Individual; Individual Differences; Industry; innovate; innovation; innovative; intent to die; juvenile; juvenile human; Knowledge; Label; Laboratories; Lead; Manias; Manic; manic depressive disorder; manic depressive illness; Manic State; Medication; Mental disorders; Mental health disorders; mental illness; Meta-Analyses; Meta-Analysis; Methods; Moods; National Institute of Mental Health; National Institute of Mental Health (U.S.); NIMH; non fatal attempt; novel; Obsessive-Compulsive Disorder; Obsessive-Compulsive Neurosis; Odds Ratio; Organ System, Cardiovascular; Outcome; Participant; Patients; Pb element; PBO; pediatric; Performance; Pharmaceutic Preparations; Pharmaceutical Preparations; placebo controlled study; placebo controlled trial; Placebos; primary care setting; Psychiatric Disease; Psychiatric Disorder; psychological disorder; Psychomotor Agitation; Psychomotor Hyperactivity; Psychomotor Restlessness; Psychosis, Manic-Depressive; R01 Mechanism; R01 Program; randomized controlled study; Randomized Controlled Trials; Recording of previous events; relational database; Relative; Relative (related person); Relative Odds; Reporting; Research; Research Grants; Research Project Grants; Research Projects; Research Projects, R-Series; Restlessness; Risk; Risk Ratio; RPG; Safety; Schools; Selective serotonin re-uptake inhibitor; Selective Serotonin Reuptake Inhibitor; Separation Anxiety Disorder; serotonin reuptake inhibitor; Severities; Severity of illness; sex; sham therapy; Sham Treatment; side effect; Social Functioning; Social Phobia; sound perception; Specific qualifier value; Specified; SSRI; SUBGP; Subgroup; substance abuse; Substance abuse problem; suicidal attempt; suicidal ideation; suicidal thinking; Suicidal thoughts; suicidality; Suicide; Suicide attempt; suicide ideation; Symptoms of depression; Testing; therapy adverse effect; thoughts about suicide; Time; treatment adverse effect; treatment effect; Treatment Side Effects; trial comparing; United States Food and Drug Administration; United States National Institute of Mental Health; Unspecified Mental Disorder; USFDA; Vascular, Heart; Weight; Work; youngster; Youth; Youth 10-21
Project start date: 2008-07-11
Project end date: 2011-04-30
Budget start date: 1-MAY-2009
Budget end date: 30-APR-2011
PFA/PA: PA-06-180
5R03MH083248-02 (2009): $72000
BDNF GENOTYPE, CORTICAL PLASTICITY AND RECOVERY FROM STROKE
A Jeffrey, Associate Professor
Arizona State University-tempe Campuscity: Tempe country: United States (us)
Grant 5R01NS058755-05 from National Institute Of Neurological Disorders And Stroke
Abstract: Stroke the third largest cause of death and is a leading cause of serious, long-term disability in the United States and worldwide. Of the 700,000 Americans who will survive a stroke this year, 70% receive some form of motor rehabilitation. However, the efficacy of current motor rehabilitation interventions is highly variable and reflects our lack of understanding of the neural and behavioral signals driving functional recovery. Motor recovery is supported by functional compensation within residual motor areas including primary motor cortex. The neural mechanisms underlying functional reorganization within motor cortex involve synaptic plasticity within cortical circuitry that is driven by specific neural signaling pathways. We hypothesize that some of the variability in the efficacy of motor rehabilitation interventions is due to inherent differences in the capacity for experience-dependent plasticity. Specifically, polymorphisms within genes that govern the activity of neural signaling pathways mediating synaptic plasticity can influence the rate and level of motor recovery after stroke. The goals of the proposed set of experiments are to characterize the relationship between genotype, cortical plasticity and motor performance. The studies will use blood genotyping, transcranial magnetic stimulation and extensive motor training/testing to examine determine how naturally occurring polymorphisms in the Brain Derived Neurotrophic Factor (BDNF) gene, known to be involved in mediating cortical plasticity, influence the capacity for cortical plasticity, age related decrements in motor performance and capacity for motor recovery after stroke. The experiments will be conducted in both young and old subjects with or without the polymorphism. We hypothesize that age related decrements in motor status and motor impairments after stroke will be exacerbated in polymorphic individuals and that this represents a compromised capacity for compensation that occurs in response to age and stroke related declines in neural function. This process is particularly important for stroke victims receiving rehabilitation to improve motor function. The short term goal of these experiments is to establish the baseline role of these different genotypes in experience-dependent plasticity in the intact brain. The long term goal of this research program is to determine how genotype may influence the capacity for motor recovery after stroke Using transcranial magnetic stimulation we will examine changes in corticospinal output in response to motor training in young, middle aged and old subjects with three variants of the BDNF genotype. We will further examine the relationship between experience- dependent cortical plasticity, motor function and age. Finally we will examine how the capacity for rehabilitation-dependent motor recovery in stroke patients varies as a function of BDNF genotype
Keywords: Adult; Age; age related; aged; Aging; Alleles; American; Area; arm; Automobile Driving; base; Base of the Brain; Behavioral; Blood; Brain; Brain Mapping; Brain-Derived Neurotrophic Factor; Cause of Death; Codon Nucleotides; Data; Demographic Factors; Digit structure; disability; Elderly; Evaluation; Event; Exercise; experience; Financial compensation; follow-up; functional status; Genes; Genetic Polymorphism; Genotype; Goals; Hand; healthy aging; Human; human subject; improved; Individual; Infarction; Intervention; Learning; Lesion; Location; Maps; Measures; Mediating; Methionine; middle age; Motor; Motor Cortex; motor impairment; motor skill learning; Motor Skills; Movement; Nature; Nervous System Trauma; neural circuit; neuromechanism; neurophysiology; Neurophysiology - biologic function; Output; Participant; Patients; Pattern; Performance; Persons; Phase III Clinical Trials; Phenotype; Plastics; Process; programs; Publishing; Recovery; Recovery of Function; Rehabilitation therapy; relating to nervous system; Research; research study; Residual state; response; Role; Sensory; Signal Pathway; Signal Transduction; Single Nucleotide Polymorphism; Source; stroke; stroke recovery; Synaptic plasticity; Testing; Time; Training; Transcranial magnetic stimulation; United States; Valine; valylvaline; Variant; Work
Project start date: 2008-03-15
Project end date: 2012-02-28
Budget start date: 1-MAR-2011
Budget end date: 28-FEB-2012
PFA/PA: PA-07-070
5R01NS058755-05 (2011): $384758
TWEAK-FN14 SIGNALING IN THE TUMOR MICROENVIRONMENT
A Jeffrey, Professor
University Of Maryland Baltimorecity: Baltimore country: United States (us)
Grant 4R01CA130967-03 from National Cancer Institute
Abstract: Solid tumors are complex tissues containing both neoplastic tumor cells and non-neoplastic cell types (e.g., vascular endothelial cells (EC), fibroblasts and macrophages) and the interactions between these cells can regulate tumor progression. For example, tumor cells produce multiple proteins that act in a paracrine manner to influence neighboring EC. Some of the proteins induce angiogenesis, which is crucial for primary tumor growth and metastasis, while others trigger immune system cell infiltration, which has both pro- and anti-tumorigenic effects. In this proposal, we describe experiments to investigate whether the cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) may play a multifunctional role in the tumor microenvironment. TWEAK expression has been detected in human tumor cells and tumor-associated macrophages, and these cells are likely the predominant sources of this cytokine in tumor tissue. TWEAK, acting via binding to the fibroblast growth factor-inducible 14 (Fn14) cell surface receptor, is an angiogenic factor in vivo. Additionally, since TWEAK treatment of EC activates the nuclear factor-?B (NF-?B) signaling pathway and promotes pro-inflammatory molecule production, this cytokine may also be a pro-inflammatory factor in vivo. In consideration of these and other findings, we hypothesize that the TWEAK-Fn14 signaling system may play an important role in both tumor angiogenesis and inflammation. Specifically, we propose that TWEAK acts at two phases of tumor development. In phase 1, tumor cell-derived TWEAK functions primarily as a paracrine regulator of EC activation, triggering both tumor angiogenesis and immune cell infiltration. In phase 2, immune system cells within the tumor stroma, in particular blood monocyte-derived macrophages, become an important secondary source of this cytokine. This TWEAK protein can also act on EC, thereby further contributing to tumor angiogenesis and persistent monocyte infiltration. TWEAK released from both cellular sources may also act on the tumor cells themselves, and all of these interactions will ultimately contribute to tumor growth and metastasis. Four Specific Aims have been formulated to test our hypothesis. These Aims are (1) To determine if TWEAK can induce pro-angiogenic and pro-inflammatory cellular responses in vitro, and to investigate if TWEAK activity is dependent on NF-?B pathway activation, (2) To determine whether TWEAK delivered into the tumor microenvironment can stimulate angiogenesis, inflammation, and tumor growth, and to investigate if these effects are dependent on NF-?B activation, (3) To determine whether TWEAK present in the tumor microenvironment promotes tumor growth, at least in part, by acting on non-neoplastic host cells and to determine if TWEAK produced by host immune cells contributes to tumor growth, and (4) To determine if TWEAK activity contributes to tumorigenesis in a spontaneous mammary cancer model and to investigate whether TWEAK antagonist administration can inhibit tumor growth in vivo. The proposed studies should provide important, novel information on the role of TWEAK and Fn14 in the tumor microenvironment and will provide insight into whether TWEAK is a potential therapeutic target for human cancer. Cancer is the second leading cause of mortality in the USA. Solid tumors are complex tissues containing both "transformed" tumor cells and "normal" cell types such as the vascular endothelial cells that line blood vessels and blood-derived immune system cells that infiltrate the tumor tissue. Previous studies have revealed that interactions between these different cell types can regulate tumor progression. In this application, we propose to investigate whether a particular cytokine, named TWEAK, is produced by multiple cell types in the tumor microenvironment and acts as an important stimulatory molecule contributing to blood vessel formation, tumor inflammation, and ultimately tumor growth
Keywords: angiogenesis; Angiogenic Factor; Apoptosis Promoter; Binding (Molecular Function); Blood; Blood Vessels; Breast Cancer Model; Cell Line; Cell Surface Receptors; cell type; Cells; Complex; cytokine; Development; Endothelial Cells; Fibroblast Growth Factor; Fibroblasts; Health; Human; Immune; Immune system; In Vitro; in vivo; Infiltration; Inflammation; Inflammatory; insight; macrophage; Malignant Neoplasms; monocyte; Mortality Vital Statistics; Names; Neoplasm Metastasis; neoplastic; neoplastic cell; Normal Cell; novel; Nuclear; paracrine; Pathway interactions; Phase; Play; Primary Neoplasm; Production; Proteins; research study; response; Role; Signal Pathway; Signal Transduction; Solid Neoplasm; Source; System; Testing; therapeutic target; Tissues; tumor; Tumor Angiogenesis; tumor growth; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; tumor progression; Tumor Tissue; tumorigenesis; tumorigenic; Vascular Endothelial Cell
Project start date: 2009-05-07
Project end date: 2013-04-30
PFA/PA: PA-07-070
4R01CA130967-03 (2011): $300875
ROLE OF STAT PROTEINS IN MAPK SIGNAL TRANSDUCTION PATHWAYS
A Jeffrey, Professor
Oklahoma State University Stillwatercity: Stillwater country: United States (us)
Grant 1R15GM097717-01 from National Institute Of General Medical Sciences
Abstract: Signal transduction pathways mediated by G proteins and MAP kinases (mitogen activated protein kinases, MAPKs) have been associated with the regulation of cell growth and differentiation and the development of diseases such as cancer, cardiac hypertrophy, and obesity. These signaling proteins and STAT (signal transducer and activator of transcription) proteins have been identified in a wide range of eukaryotes but the role of STAT proteins in G protein/MAPK pathways remains to be determined. The proposed research will investigate the regulation of STAT proteins in MAPK mutants in Dictyostelium development because recent studies suggest an overlap in MAPK and STAT function in the regulation of tissue specific gene expression. The regulation of STAT proteins through MAPK pathways will be examined for direct interactions involving MAPK-specific docking and phosphorylation sites on STAT proteins and for indirection interactions involving changes in cAMP signaling. These studies will determine the importance and specificity of STAT proteins in G protein/MAPK pathways that control gene expression and cell differentiation. These studies will challenge previous signaling paradigms of MAPKs and STAT proteins functioning in separate pathways. MAP kinases coordinate cell growth and differentiation by regulating other signaling proteins such as transcription factors. Alterations in these signaling pathways can lead to oncogenesis, heart disease, and several developmental diseases. This study will examine MAPK regulation of STAT proteins, a class of transcription factors not previously associated with MAPK signaling pathways. The results of this research will provide important insights into the regulation of MAPK pathways and the treatment of related diseases
Keywords: Biochemical; Cell Differentiation process; cell growth; cell growth regulation; Cell physiology; Cells; Complex; Cyclic AMP; cytokine; Development; Developmental Gene; Dictyostelium; Disease; Docking; Eukaryota; G-Protein-Coupled Receptors; Gene Expression; Genetic; Growth Factor; GTP-Binding Proteins; Heart Diseases; Heart Hypertrophy; insight; Janus kinase 1; Lead; Malignant Neoplasms; MAPK1 gene; MAPK3 gene; Mediating; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; mutant; Obesity; Organism; Pathway interactions; Phenotype; phosphoric diester hydrolase; Phosphorylation; Phosphorylation Site; protein function; Proteins; Regulation; Research; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Protein; Specificity; STAT protein; Testing; Tissue-Specific Gene Expression; transcription factor; tumorigenesis
Relevance: MAP kinases coordinate cell growth and differentiation by regulating other signaling proteins such as transcription factors. Alterations in these signaling pathways can lead to oncogenesis, heart disease, and several developmental diseases. This study will examine MAPK regulation of STAT proteins, a class of transcription factors not previously associated with MAPK signaling pathways. The results of this research will provide important insights into the regulation of MAPK pathways and the treatment of related diseases
Project start date: 2011-09-02
Project end date: 2013-08-31
Budget start date: 2-SEP-2011
Budget end date: 31-AUG-2013
PFA/PA: PA-10-070
1R15GM097717-01 (2011): $276139
IMAGE RECONSTRUCTION FOR DYMANIC CONTRAST-ENHANCED MR IMAGING OF
A Jeffrey, Professor
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Abstract: Seeinstructions) Dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) of breast cancer patients has shown considerable promise in aiding diagnoses of breast lesions and characterizing treatment response. The challenge in DCE breast imaging is the need for both good temporal resolution to capture tracer kinetic properties and good spatial resolution for visualizing morphology. Traditional dynamic methods in MRI acquire incomplete k-space data at each time point, and use k-space temporal interpolation (or data sharing) to form "complete" k-space datasets prior to Fourier reconstruction. We propose to investigate model-based image reconstruction methods that avoid k-space interpolation by estimating the object model parameters that best fit the available k-space data. These reconstruction methods will incorporate parallel imaging techniques. They will also be extended to account for nonrigid deformations due to patient motion during the scan using novel methods for joint estimation of motion parameters and image intensity parameters. The methods will be evaluated using computer simulations, phantom studies, and human DCE-MRI scan data. The human data will be collected as part of Project 1 and will include DCE-MRI scans of breast cancer patients undergoing neoadjuvant chemotherapy, where early prediction of tumor response is of clinical importance. The proposed methods have the potential to improve image quality both in breast DCE-MRI as well as other dynamic MR applications. RELEVANCE (See instructions) The relevance of this research to public health is that improving the quality of MR images through more sophisticated data processing may lead to more accurate diagnosis and treatment of patients with breast cancer and other diseases
Keywords: Accounting; Algorithms; Articulation; Artifacts; base; Biopsy Sample; Biopsy Specimen; Blinded; Breast; breast lesion; Cancer of Breast; Cancer Patient; Cancers; Characteristics; chemotherapy; Clinical; Compensation; computational modeling; computational models; computational simulation; computer based models; Computer Simulation; computerized data processing; computerized modeling; Computerized Models; computerized simulation; cost; Data; data processing; Data Set; data space; Dataset; Diagnosis; digital; Disease; disease/disorder; Disorder; Drug Formulations; Financial compensation; Formulation; Formulations, Drug; Freedom; Goals; heavy metal lead; heavy metal Pb; Histopathology; Human; human data; Human, General; Image; Image Reconstructions; image registration; imaging; Imaging Procedures; Imaging Techniques; improved; in silico; Induction Therapy; Instruction; Investigators; Joints; Kinetic; Kinetics; Lead; Lesion of breast; Liberty; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; malignancy; malignant breast neoplasm; Malignant neoplasm of breast; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Breast; Man (Taxonomy); Man, Modern; Mathematical Model Simulation; Mathematical Models and Simulations; Measures; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Methods; Methods and Techniques; Methods, Other; Metric; Modeling; Models, Computer; Modification; Morphologic artifacts; Morphology; Motion; MR Imaging; MR Tomography; MRI; NEOADJ; Neoadjuvant; Neoadjuvant Therapy; Neoadjuvant Treatment; neoplasm/cancer; NMR Imaging; NMR Tomography; novel; Nuclear Magnetic Resonance Imaging; object motion; operation; Patients; Pattern; Pb element; Performance; Pilot Projects; pilot study; Property; Property, LOINC Axis 2; Public Health; public health medicine (field); Radial; radiologist; RDST; Reader; reconstruction; Research; Research Personnel; Researchers; Resolution; response; Rotation; Sampling; Scanning; Series; sharing data; signal processing; simulation; Simulation, Computer based; Tag; Technics, Imaging; Techniques; Time; Tracer; Translations; treatment response; tumor; virtual simulation; Zeugmatography
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
5P01CA087634-08_7891 (2011): $262776
PREVENTION OF HIV INFECTION IN HIGH-RISK SOCIAL NETWORKS OF AFRICAN AMERICAN MSM
A Jeffrey, Professor And Director
Medical College Of Wisconsincity: Milwaukee country: United States (us)
Grant 5R01MH089128-02 from National Institute Of Mental Health
Abstract: Risk for HIV infection in the United States falls along sharp lines of disparity related to sexual orientation and race/ethnicity. HIV infection has always taken a heavy toll on men who have sex with men (MSM) and also on African Americans. However, HIV incidence disparity is most striking of all for MSM who are also African American, a segment that probably accounts for less than one percent of the American population but fully 25% of all new HIV infections in the United States. Surprisingly, very few HIV prevention interventions designed for African American MSM have been undertaken, and most existing approaches have relied on individual or small-group risk reduction counseling. These existing models have limited cultural and practical suitability for reaching high-risk African American MSM who are hidden in the community and unlikely to seek out sexual risk reduction counseling. Interventions directed to individuals alone also do not attend sufficiently to the important influence played by social norms and social network factors on risk behavior. In contrast to individual counseling models, HIV prevention interventions that are directed to social networks of Black MSM in the community and that work through natural influence channels within these networks hold the potential for reaching deeply into hidden and vulnerable populations of African American MSM. Network-level HIV prevention interventions rely on oral communication traditions and cultural models appropriate in minority communities, and can strengthen social network normative support for risk reduction. Following a 1-year formative research phase that will provide data needed to contextualize the study´s recruitment, assessment, and intervention content and delivery methods, we will undertake a social network-level intervention outcome trial in 3 cities Milwaukee, Cleveland, and Miami. Project-wide, 24 sociocentric networks of African American MSM-each expected to be composed of approximately 40 people (total n=960 participants)-will be recruited. 12 of the networks (n=480 participants) will be randomized to a comparison condition and receive HIV/STD testing, treatment, and individual counseling. The other 12 networks (n=480) will receive the same counseling and testing and also a social network intervention that identifies, trains, and engages empirically-identified influence leaders of each network to deliver ongoing, theory-based, and culturally tailored HIV prevention advice, recommendations, and support to other network members. The study will determine the comparative effectiveness of the social network intervention to the counseling, testing, and treatment comparison condition on measures of sexual risk, substance use associated with sexual risk behavior, and STD/HIV incidence assessed with laboratory measures at 6- and 18-month followup points. The study aim is to develop and determine the efficacy of an intervention modality capable of reaching and preventing HIV among high-risk African American MSM in the community. 56,000 Americans continue to contract HIV each year, and African American MSM account for a far disproportionate number of incident infections. Public health efforts to reduce HIV incidence in the United States require the development of new prevention approaches delivered using modalities that can target and reach those population segments at greatest vulnerability. If successful, this research will identify an HIV prevention intervention approach, practical for public health service providers, that lends itself well to rapid uptake and use by CBOs, health departments, and minority organizations concerned about AIDS
Keywords: Accounting; Acquired Immunodeficiency Syndrome; Address; Advocate; Affect; African American; AIDS prevention; AIDS/HIV problem; Alcohol or Other Drugs use; American; Anus; arm; base; behavior change; Behavior Therapy; Biological; Bisexual; Caring; Centers for Disease Control and Prevention (U.S.); Characteristics; Cities; Collaborations; Color; Communities; Community Participation; comparative effectiveness; condoms; contextual factors; Contracts; cost; cost effectiveness; Counseling; Country; Data; Development; Diagnosis; Diffuse; directed attention; Disease; Drug usage; Eastern Europe; Economics; Employee Strikes; Enrollment; Epidemic; ethnic minority population; Ethnicity aspects; falls; Foundations; Frequencies (time pattern); Friends; Gays; group counseling; Health; health disparity; Health Personnel; high risk; high risk sexual behavior; HIV; HIV Infections; HIV/STD; Human immunodeficiency virus test; Incidence; indexing; Individual; Infection; informant; International; Intervention; Intervention Trial; Interview; Laboratories; Language; Life Style; man; Measures; member; men; men who have sex with men; Methods; Minority; Modality; Modeling; novel; oral communication; Outcome; Participant; Persons; Phase; Pilot Projects; Play; Population; Preparation; Prevalence; prevent; Prevention; Prevention approach; Preventive Intervention; primary outcome; Procedures; programs; prospective; Provider; public health medicine (field); public health relevance; public health research; Publishing; Race; Randomized; randomized trial; Recommendation; Recording of previous events; Recruitment Activity; Reporting; Research; Risk; Risk Behaviors; Risk Reduction; Risk Reduction Behavior; Sampling; Services; sex; Sex Behavior; Sex Orientation; sex risk; Shock; Site; social; Social Network; social stigma; Specimen; Stigmata; Structure; Testing; theories; therapy design; Training; Treatment Efficacy; United States; United States Public Health Service; uptake; Visit; Vulnerable Populations; Work
Relevance: PREVENTION OF HIV INFECTION IN HIGH-RISK SOCIAL NETWORKS OF AFRICAN AMERICAN MSM 56,000 Americans continue to contract HIV each year, and African American MSM account for a far disproportionate number of incident infections. Public health efforts to reduce HIV incidence in the United States require the development of new prevention approaches delivered using modalities that can target and reach those population segments at greatest vulnerability. If successful, this research will identify an HIV prevention intervention approach, practical for public health service providers, that lends itself well to rapid uptake and use by CBOs, health departments, and minority organizations concerned about AIDS
Project start date: 2010-09-28
Project end date: 2015-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-07-409
5R01MH089128-02 (2011): $1077809
RHO GEFS IN CELLULAR PROLIFERATION AND TRANSFORMATION
A Jeffrey
University Of Texas Hlth Sci Ctr Houstoncity: Houston country: United States (us)
Grant 3R01CA116356-05S1 from National Cancer Institute
Abstract: Rho family small G protein activation has been implicated in the development of cancer and in metastatic progression. Rho protein activation is controlled by a family of enzymes known as guanine nucleotide exchange factors (Rho GEFs), so understanding the mechanisms regulating Rho GEF activity is critical to devising strategies to block Rho protein-mediated transformation. NET1 is a nuclear Rho GEF that is specific for the RhoA subfamily of small G proteins. Overexpression of NET1 results in its mislocalization in the cytoplasm, and stimulates constitutive RhoA activation and cell transformation. We have observed that NET1 isoforms are overexpressed in primary breast tumors, and that overexpression of NET1 proteins in breast cancer cell lines dramatically stimulates their proliferation. We have also observed that NET1 requires a C-terminal PDZ binding site to stimulate cell proliferation and transformation, and that this binding site mediates interaction with a protein complex consisting of the tumor suppressor Dlg1, the related protein Cask, and the DNA modifying enzyme Topo I. Since Dlg1 is a requisite target for oncoproteins from cancer causing viruses such as the human papilloma virus and the human T cell leukemia virus 1, the interaction between NET1 and Dlg1 is likely to be especially important to the mechanism by which NET1 controls cell proliferation. The hypothesis driving the proposed research is that overexpression of NET1 causes its mislocalization in the cytoplasm, and results in the constitutive activation of RhoA and an inhibition of the tumor suppressor function of Dlg1. We will address this hypothesis in the following specific aims. In Aim1 we will characterize the interaction of NET1 isoforms with Dlg1, Cask and Topo I in vitro and in breast epithelial cells. In Aim 2 we will elucidate how the phosphorylation of NET1 isoforms by regulatory kinases controls the interaction of NET1 with Dlg1. In Aim 3 we will examine the effects of NET1 overexpression, complex formation with Dlg1, Cask and Topo I, and NET1 phosphorylation on breast epithelial cell proliferation and transformation. Completion of these aims will delineate a unique and previously unrecognized role for NET1 and Dlg1 in controlling breast epithelial cell transformation, and identify potential new targets for intervention in this disease
Keywords: Address; Affect; Automobile Driving; base; Binding Sites; Breast; Breast Cancer Cell; C-terminal; Cancer cell line; Cancer Etiology; Cell Cycle Progression; cell motility; Cell Proliferation; cell transformation; Complex; Cytoplasm; Data; Development; Disease; DNA; Enzymes; Epithelial Cell Proliferation; Epithelial Cells; Family; genetic regulatory protein; Goals; Guanine Nucleotide Exchange Factors; Human; Human Papillomavirus; Human T-Cell Leukemia Viruses; human TOP1 protein; In Vitro; in vitro activity; Intervention; malignant breast neoplasm; Malignant Neoplasms; Mammary Neoplasms; Mediating; metaplastic cell transformation; Monomeric GTP-Binding Proteins; Neuroepithelioma; Normal Cell; Normal tissue morphology; Nuclear; Oncogene Proteins; overexpression; Phosphorylation; Phosphotransferases; protein activation; protein complex; Protein Isoforms; Protein Kinase; Proteins; Regulation; Research; rho; RNA Splicing; Role; Site; tumor; Tumor Suppressor Proteins; Type I DNA Topoisomerases; Variant; Virus
Project start date: 2007-06-01
Project end date: 2012-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
3R01CA116356-05S1 (2011): $58206
5R01CA116356-05 (2011): $227669
Sponsored Links Excellgen http://Excellgen.com
LARGE-SCALE DISCOVERY OF FUNCTIONAL GENETIC VARIATION IN RHESUS MACAQUES
A Jeffrey, Associate Professor
Baylor College Of Medicinecity: Houston country: United States (us)
Grant 1R24RR032329-01 from National Center For Research Resources
Abstract: Rhesus macaques (Macaca mulatta) are the most widely used nonhuman primate in biomedical research. Rhesus are critically important in efforts to understand the pathogenesis of HIV-AIDS, to develop novel treatments and new vaccines against HIV infection. In addition, rhesus macaques are commonly used in studies of basic neurobiology, metabolic diseases such as diabetes and osteoporosis, and reproductive biology. Rhesus monkeys are important in analyses of stem cell biology. This species is also frequently used as an animal model in studies related to alcoholism, drug addiction, anxiety disorders and depression. This proposed project will dramatically increase the value and significance of this primate species for all types of biomedical research by generating a substantial amount of new information about functional genetic variation among rhesus macaques. It is now well established that genetic differences among people influence their risk of developing common diseases such as those listed above, including infectious diseases. Genetic variation can also influence the progression of disease and the responses of different people to a specific treatment. We will facilitate research on the genetic basis of disease susceptibility and response to treatment by identifying large numbers of new DNA sequence variants in functional genes within the rhesus genome. To accomplish this, we will sequence the exome (all functional gene exons) from 96 unrelated rhesus macaques, both Indian-origin and Chinese-origin animals. We will also produce whole genome sequences for 8 of those 96 animals. The exome and whole genome data will be used to identify new DNA sequence variation present in this species. We will also sequence RNA from the lymphocytes of all 96 animals to begin assessment of individual variation in gene expression within that tissue, and to correlate differential RNA expression with DNA sequence variation in the relevant genes. All the data generated will be made publically available through appropriate NCBl databases (e.g. Short Read Archive, dbVAR and dbSNP) and by creating our own public searchable on-line database of rhesus genetic variation. PUBLIC HEALTH RELEVANCE This project will advance and facilitate research in various fields by generating a large amount of novel and valuable information about genetic variation within rhesus macaques. This species is important for research related to many different human health problems. Increased knowledge of genetic variation in this primate species will allow researchers to conduct innovative studies of genetic effects on health and disease
Keywords: Acquired Immunodeficiency Syndrome; Alcoholism; Animal Model; Animals; Anxiety Disorders; Archives; base; Biological Factors; Biomedical Research; Cataloging; Catalogs; Chinese People; Communicable Diseases; Communities; Data; Databases; Development; developmental psychobiology; Diabetes Mellitus; Disease; Disease Progression; Disease susceptibility; DNA; DNA Sequence; Drug Addiction; Exhibits; exome; Exons; Funding; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genome; genome sequencing; Genomics; Goals; Health; HIV; HIV Infections; HIV vaccine; Human; Individual; innovation; interest; Investigation; Knowledge; Leukocytes; Lymphocyte; Macaca; Macaca mulatta; Mental Depression; Metabolic Diseases; Methods; Modeling; Molecular Genetics; National Human Genome Research Institute; Neurobiology; Neurosciences; nonhuman primate; novel; novel vaccines; Obesity; Osteoporosis; Pan Genus; Pathogenesis; Primates; Principal Investigator; Reading; Reproductive Biology; Reproductive Endocrinology; Research; Research Personnel; Resources; response; Risk; RNA Sequences; SIV; stem cell biology; Subfamily lentivirinae; Tissues; United States National Institutes of Health; Variant; Variation (Genetics)
Relevance: This project will advance and facilitate research in various fields by generating a large amount of novel and valuable information about genetic variation within rhesus macaques. This species is important for research related to many different human health problems. Increased knowledge of genetic variation in this primate species will allow researchers to conduct innovative studies of genetic effects on health and disease
Project start date: 2011-09-01
Project end date: 2015-06-30
Budget start date: 1-SEP-2011
Budget end date: 30-JUN-2012
PFA/PA: PAR-10-289
1R24RR032329-01 (2011): $549490
HIV PREVENTION WITHIN HIGH-RISK SOCIAL NETWORKS
A Jeffrey, Professor And Director
Medical College Of Wisconsincity: Milwaukee country: United States (us)
Grant 5R01DA023854-10 from National Institute On Drug Abuse
Abstract: Post-Soviet countries have experienced a very recent and very rapid rise in HIV infection rates, and parts of the region now have disease incidence among the highest in the world. HIV prevention efforts undertaken now can avert the unfolding of an even greater epidemic. Social network intervention approaches are culturally well-suited to Eastern Europe, a region characterized by dramatic and often difficult socioeconomic and cultural transformations, and where individuals have long relied on their social networks for social support and trusted advice. Over the past 4 years, our international collaborative team has successfully carried out studies evaluating the impact of social network HIV prevention interventions with young men who have sex with men (YMSM), ethnic minority Roma (Gypsies), and young high-risk heterosexual adult (YHA) women and men in Russia, Bulgaria, and Hungary. This competitive renewal application requests support to undertake a new generation of social network intervention research trials with these populations. The study will use a 3-wave snowball enrollment method to recruit 24 social networks of YMSM, Roma, and YHAs, each expected to include approximately 60 persons (n=1,440). All participants will complete baseline network structure and sociometric measures and risk assessment interviews; be offered testing and treatment for STDs and HIV; and receive risk reduction counseling. 20% of participants in each network will be identified as leaders based on their high sociometric standing and high connectedness with others in the network. Networks will then be randomized in equal numbers to experimental and control conditions (n=12 networks, 720 participants per arm). Leaders will attend a 9-session program that trains and guides them in delivering theory-based risk reduction recommendations to their network members. The messages will target network members´ risk reduction knowledge, attitudes, intentions, perceived norms, and self-efficacy. Leaders of control networks will attend an attention-matched intervention unrelated to AIDS. At 3- and 15- month follow up, the cohort will be assessed to determine change in risk behavior characteristics and to determine cumulative STD/HIV incidence. We hypothesize greater risk behavior reduction and lower disease incidence in experimental networks. In addition to its cultural relevance in Eastern Europe, the trial will inform the development of new HIV prevention strategies to reach high-risk population segments in the U.S
Keywords: Accounting; Acquired Immunodeficiency Syndrome; Adult; AIDS prevention; AIDS/HIV problem; Alcohol or Other Drugs use; Anus; arm; Attention; Attitude; base; behavior change; Behavioral; Blood specimen; Bulgaria; Caring; Characteristics; Chlamydia; Cognitive; cohort; Collaborations; Communities; Community Health; Community Networks; condoms; Contracts; Counseling; Country; Development; Disadvantaged; Disease; Eastern Europe; Educational Intervention; Enrollment; Epidemic; Ethics; ethnic minority population; experience; follow-up; Frequencies (time pattern); Friendships; Funding; Generations; Gonorrhea; Government; group counseling; Gypsies; Heterosexuals; high risk; HIV; HIV Infections; HIV/STD; Hungary; Incidence; Individual; International; Intervention; Intervention Studies; Intervention Trial; Interview; Knowledge; Language; Light; Maps; Measures; member; men; men who have sex with men; Methods; Modeling; Participant; peer; Persons; Play; Population; Population Intervention; Prevalence; Prevention program; Prevention strategy; Preventive Intervention; Procedures; psychosocial; public health medicine (field); Randomized; Randomized Controlled Trials; Recommendation; Recording of previous events; Recruitment Activity; Relative (related person); Request for Applications; Research; Risk; Risk Assessment; Risk Behaviors; Risk Reduction; Risk Reduction Behavior; Role; Russia; Safety; Self Efficacy; Services; sex risk; Site; social; Social Environment; Social Network; Social support; socioeconomics; Source; Structure; Syphilis; Techniques; Testing; theories; Training; Training Programs; Trust; United States; Urine; Vagina; Woman; Work; young adult
Project start date: 2001-06-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5R01DA023854-10 (2011): $537618
CENTER FOR AIDS INTERVENTION RESEARCH CORE SUPPORT
A Jeffrey, Professor And Director
Medical College Of Wisconsincity: Milwaukee country: United States (us)
Grant 5P30MH052776-18 from National Institute Of Mental Health
Abstract: OVERALL This revised P30 application seeks the competitive renewal for 2009-2014 of the Center for AIDS Intervention Research at the Medical College of Wisconsin as an HIV behavioral research center. Throughout its history, CAIR´s thematic mission has been the conceptualization, conduct, and rigorous evaluation of HIV primary and secondary prevention interventions, and the dissemination of research findings to both the scientific community and service providers. The Center structure supports the efforts of an interdisciplinary team of HIV prevention investigators, and CAIR has been highly productive and a strong regional, national, and international resource in the areas of research, training, and service to public health providers. Center investigators have made substantial contributions in the conduct of HIV primary and secondary prevention interventions in vulnerable populations in the United States, Eastern Europe and other regions of the world; have advanced our scientific knowledge of how to transfer research-based prevention models to service providers nationally and internationally; and have undertaken rigorous lines of behavioral and social science, methodological, and cost-effectiveness research applied to HIV prevention. To support continued excellence in these and other emerging new areas that we will pursue in the years ahead, we propose a structure that brings together teams of interdisciplinary scientists and provides resources in the following Core areas Administrative Core, responsible for scientific and administrative leadership of the Center; Developmental Core, which supports preliminary studies, internal peer review, and Center seminars and conferences; Quantitative Methods Core, with resources that support central data management, analysis, and biostatistical consultation; Qualitative Methods Core, which provides qualitative and social science support to CAIR investigators; Intervention Support and Dissemination Core, with functions that meet the needs of intervention studies and transfer research advances to service providers and others outside CAIR; International Research and Support Core, which facilitates international initiatives; and Cost-Effectiveness Modeling Core, which supports the conduct of HIV prevention economic evaluation research
Relevance: Success in public health efforts to curb the toll taken by HIV/AIDS in this country and throughout the world requires the thoughtful integration of behavioral and social science with advances being made in the medical arena. CAIR´s thematic mission addresses public health goals of preventing HIV/AIDS in populations and communities most vulnerable to the disease. The Center´s Core structure brings added and synergistic value to interdisciplinary research on AIDS, and CAIR serves as a regional, national, and intprnational public health resource
Project start date: 1997-05-01
Project end date: 2014-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PAR-08-009
5P30MH052776-18 (2011): $2171023
IMMUNOMODULATION OF TRANSPLANT REJECTION BY ANTI-CD3 MAB
A Jeffrey, Professor
University Of California San Franciscocity: San Francisco country: United States (us)
Grant 5R37AI046643-11 from National Institute Of Allergy And Infectious Diseases
Abstract: OKT3 therapy for the treatment of organ graft rejection is complicated by severe first dose side effects caused by T cell activation-induced cytokine release in vivo. Moreover, OKT3 causes pan-immunosuppression that can lead to increased infections and cancer. The investigators have developed a novel Fc receptor (FcR) non-binding form of anti-murine CD3 mAb, 2C11-IgG3, which suppresses immune responses in the absence of first dose side effects. In vitro, 2C11-IgG3 has short-lived effects on naive T cells, but delivers a partial signal to activated T cells that results in clonal inactivation of Th1 cells, proliferation/ cytokine production by Th2 cells, and Th2 deviation of undifferentiated T cells. Biochemical analyses of the early activation events in both T cell subsets show an identical pattern of partial phosphorylation of T cell receptor (TCR) zeta and ZAP-70 similar to that observed in T cells treated with altered CD4 receptor blockade during T cell activation. These results suggest that this novel TCR antagonist can differentially alter the intracellular signals that regulate Th1 and Th2 development selectively on antigen-experienced T cells. The investigators hypothesize that unbalanced biochemical signaling, exemplified by this mAb, is a common mechanism to regulate T cell differentiation and tolerance induction in vivo. The proposed study will focus on several questions 1) Do the biochemical and functional changes induced by 2C11-IgG3 in vitro also occur in vivo in the allogeneic islet transplant model? 2) Can the mechanisms that regulate this process be defined? 3) What are the minimal biochemical signaling events required for Th cell differentiation? To answer these questions, proposes the following specific aims 1) Determine the in vivo effect of 2C11-IgG3 mAb on T cell signaling in the allogeneic islet transplant model. 2) Use biochemical analyses and retroviral gene transfer to define the proximal signaling events associated with clonal inactivation, cell death, and T helper subset differentiation induced by 2C11-IgG3. 3) Use biochemical analyses and retroviral gene transfer to define the distal signaling events associated with clonal inactivation, cell death, and T helper subset differentiation induced by 2C11-IgG3
Keywords: Adverse effects; Allogenic; Anaplastic; Anti CD3; Anti-CD3 Monoclonal Antibody OKT3; antibody receptor; Antigens; ATGN; Binding; Binding (Molecular Function); Biochemical; biological signal transduction; Cancers; CD3; CD3 Antigens; CD3 Complex; CD3 molecule; CD4 Antigen (P55); CD4 Antigens; CD4 Molecule; CD4 Protein; Cell Communication and Signaling; Cell Death; Cell Differentiation; Cell Differentiation process; Cell Growth in Number; Cell Multiplication; Cell Proliferation; Cell Signaling; Cellular Proliferation; Chimp; Chimpanzee; Clinical, Transplantation, Organ; cytokine; Development; Distal; Dose; Event; experience; Fc Receptor; FcR; Gene Transfer; Graft Rejection; Grafting Procedure; heavy metal lead; heavy metal Pb; helper T lymphocyte marker; host response; IgG3; immune modulation; Immune response; immunogen; immunologic reactivity control; Immunomodulation; immunoregulation; immunoresponse; immunosuppression; Immunosuppression Effect; Immunosuppressions (Physiology); Immunosuppressive Effect; In Vitro; in vivo; Infection; Intracellular Communication and Signaling; Investigators; islet; Lead; Life; Major Histocompatibility Complex Receptor; malignancy; Malignant Neoplasms; Malignant Tumor; Mammals, Mice; MHC Receptor; Mice; MoAb OKT3; Modeling; Molecular Interaction; Monoclonal Antibody OKT3; Murine; Muromonab-CD3; Muromonab-CD3 Monoclonal Antibody; Mus; Natural immunosuppression; necrocytosis; neoplasm/cancer; novel; OKT3; OKT3 antigen; OKT4 antigen; organ allograft; organ graft; Organ Transplantation; Organ Transplants; Organ Transplants, Including Bone Marrow for DCT; organ xenograft; Pan; Pan Genus; Pan Species; Pattern; Pb element; Phosphorylation; Process; Production; Protein Phosphorylation; Receptors, Antigen, T-Cell; Receptors, CD4; Receptors, Surface CD4; Research Personnel; Researchers; side effect; Signal Transduction; Signal Transduction Systems; Signaling; SRK; T-Cell Activation; T-Cell Antigen T4/Leu3; T-Cell Receptor; T-Cell Subsets; T-Cell Surface Antigen T4/Leu-3; T-Cells; T-Lymphocyte; T-Lymphocyte Subsets; T3 Antigens; T3 Complex; T3 molecule; T4 molecule; Th-1 Cell; Th-2 Cell; Th1 Cells; Th2 Cells; therapy adverse effect; thymus derived lymphocyte; Thymus-Dependent Lymphocytes; transfer of a gene; transplant; Transplant Rejection; Transplantation; Transplantation Rejection; Transplantation Surgery; treatment adverse effect; Treatment Side Effects; Type 1 Helper Cell; Type 2 Helper Cell; Undifferentiated; ZAP-70; ZAP-70 Gene
Project start date: 2000-03-01
Project end date: 2011-02-28
Budget start date: 1-MAR-2009
Budget end date: 28-FEB-2011
5R37AI046643-11 (2009): $281840
THE NRF2-ARE PATHWAY IN AMYOTROPHIC LATERAL SCLEROSIS
A Jeffrey
University Of Wisconsin Madisoncity: Madison country: United States (us)
Grant 5R01ES008089-13 from National Institute Of Environmental Health Sciences
Abstract: Nrf2 (NF-E2-related factor 2) has been demonstrated to play a central role in the gene expression of detoxification enzymes and antioxidant genes through binding the antioxidant responsive element (ARE). Importantly, in in vitro and in vivo models, this system has been shown to be effective at blocking neurotoxicity resulting from glutathione depletion, lipid peroxidation, intracellular calcium overload, excitotoxins, and disruption of the mitochondrial electron transport chain. In particular, increased levels of glutathione (GSH) seem to be a major component of the protection observed by Nrf2 activation. Glutamate-cysteine ligase catalytic (GCLC) and modifier (GCLM) subunits make up the rate-limiting enzyme complex for GSH synthesis and Nrf2 transcriptionally regulated both enzymes. Interestingly, the Nrf2-ARE pathway activation is isolated to astrocytes that confer resistance to neurons. Several studies have demonstrated that secreted GSH can protect neurons acting as an antioxidant in the extracellular compartment and boosting GSH levels in neurons by increasing the availability of precursors for GSH synthesis. We are particularly intrigued by astrocyte-motor neuron interaction and how the Nrf2-ARE pathway could be involved in this intimate relationship, as well as the level of importance of GSH to motor neuron survival, in amyotrophic lateral sclerosis (ALS). Some of the inherited forms of ALS are associated with mutations in human Cu/Zn superoxide dismutase 1 (hSOD1). Mouse models have been generated using mutant forms of hSOD1 that recapitulate much of the cellular and phenotypic changes observed in human ALS patients. We hypothesize that Nrf2-ARE activation and GSH production in the astrocyte will protect motor neurons in models of ALS in vitro and in vivo. We have generated glial fibrillary acidic protein (GFAP)-Nrf2 mice that selectively overexpress Nrf2 in astrocytes. Preliminary data in co-cultures of astrocytes and motor neurons indicate that hSOD1G93A astrocytes are "sick" and that motor neurons die when plated on these "sick" astrocytes. Strikingly, if Nrf2 is overexpressed in the same "sick" astrocytes, the motor neurons do not die. Initial in vivo studies show an increase in lifespan of the hSOD1G93A mice when crossed with GFAP-Nrf2 mice. Finally, ongoing experiments using the GCLM-/- mice are underway. In this case, hSOD1G93A mice on GCLM-/- background show dramatic muscle weakness (0 sec on wire hang) and initial signs of paralysis by 45 days of age compared to 120 days of age on a GCLM+/+ background. The specific aims of this proposal are Aim 1. To determine the significance of Nrf2 and GSH in astrocyte-mediated motor neuron survival in vitro; Aim 2. To evaluate the role of GSH in the Nrf2- mediated delay in onset and progression of disease in hSOD1G93A mice; and Aim 3. Test the efficacy of clinically relevant approaches for the treatment o ALS using viral-mediated delivery of Nrf2 or non- viral delivery of Keap1 siRNA. PUBLIC HEALTH RELEVANCE Pound 5,600 people in the United States are diagnosed with ALS every year and there are about 30,000 Americans with the disease at any given time. Approximately 80% of ALS suffers will die within 5 years of diagnosis. Thus, the lack of any significant therapeutic intervention for ALS is an important medical issue. The majority of ALS cases are sporadic with unknown cause. Environmental exposure is thought to play a major role in sporadic disease and is believed to be a principal component behind the increased incidence in ALS among Gulf War veterans and people serving in the military. Irrespective of the underlying cause of ALS, the approaches outlined in proposal are focused on a pathologic processes seen in both sporadic and familial disease, and could lead to new ways to treat ALS. In addition to looking at the onset of the disease in these animal models, specific experiments will examine disease progression that more accurately represent the human clinical situation. The hope is to gain a greater understanding of the disease process and discover ways to treat ALS that will stop or at least slow disease progression
Keywords: Age; American; Amyotrophic Lateral Sclerosis; Animal Model; Antioxidants; Astrocytes; base; Binding (Molecular Function); Biological Models; Calcium; Cell Death; Cells; Clinical; clinically relevant; Coculture Techniques; Cuprozinc Superoxide Dismutase; Data; Diagnosis; Disease; Disease Progression; Drug Metabolic Detoxication; efficacy testing; Electron Transport; Elements; Environmental Exposure; Enzymes; Excitatory Neurotoxins; extracellular; Familial disease; Free Radical Scavenging; GCLC gene; Gene Expression; Gene Expression Profiling; Gene Pool; Genes; Glial Fibrillary Acidic Protein; Glutamate-Cysteine Ligase; Glutathione; glutathione synthase; Gulf War; Health; Human; improved; In Vitro; in vivo; in vivo Model; Incidence; Inherited; Laboratories; Lead; Lipid Peroxidation; Longevity; Mediating; Medical; Military Personnel; Mitochondria; Modeling; Motor Neurons; mouse model; Multienzyme Complexes; Mus; Muscle Weakness; mutant; Mutation; NADP; Neurons; neuroprotection; neurotoxicity; NF-E2-related factor 2; Onset of illness; overexpression; Oxidative Stress; Paralysed; Pathologic Processes; Pathway interactions; Patients; Play; prevent; Process; Production; research study; Resistance; Role; Small Interfering RNA; superoxide dismutase 1; System; Testing; Therapeutic Intervention; Time; Transgenic Model; Translating; United States; Veterans; Viral
Relevance: Around 5,600 people in the United States are diagnosed with ALS every year and there are about 30,000 Americans with the disease at any given time. Approximately 80% of ALS suffers will die within 5 years of diagnosis. Thus, the lack of any significant therapeutic intervention for ALS is an important medical issue. The majority of ALS cases are sporadic with unknown cause. Environmental exposure is thought to play a major role in sporadic disease and is believed to be a principal component behind the increased incidence in ALS among Gulf War veterans and people serving in the military. Irrespective of the underlying cause of ALS, the approaches outlined in proposal are focused on a pathologic processes seen in both sporadic and familial disease, and could lead to new ways to treat ALS. In addition to looking at the onset of the disease in these animal models, specific experiments will examine disease progression that more accurately represent the human clinical situation. The hope is to gain a greater understanding of the disease process and discover ways to treat ALS that will stop or at least slow disease progression
Project start date: 1996-08-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-070
5R01ES008089-13 (2011): $360633
IDENTIFICATION OF RESISTANCE MECHANISMS TO ANAPLASTIC LYMPHOMA KINASE INHIBITORS
A Jeffrey
Massachusetts General Hospitalcity: Boston country: United States (us)
Grant 1R01CA164273-01 from National Cancer Institute
Abstract: Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths in the United States. Over the last decade, a number of new therapies targeting signaling pathways that control cell growth and survival have been developed. Some of these, particularly tyrosine kinase inhibitors (TKIs), have shown remarkable antitumor activity in select subsets of lung cancer patients. Examples include gefitinib or erlotinib for EGFR- mutant lung cancers and more recently, crizotinib (PF-02341066) for lung cancers harboring chromosomal rearrangements of ALK (anaplastic lymphoma kinase). These therapies often induce marked responses and clinical remissions; however, cancers invariably develop resistance to TKI therapy, usually within one year of treatment. This type of resistance is termed acquired resistance, and it has severely curbed the impact of these new therapies. In this application, we will focus on ALK-positive lung cancers which affect approximately 8,000 people per year in the United States alone. We have previously shown that the lung cancer patients most likely to harbor ALK rearrangements are the young, never smokers with the adenocarcinoma type of NSCLC. In a seminal phase 1 trial led by our institution, crizotinib induced significant responses in close to 60% of ALK-positive patients, and stabilized disease in an additional 30%. Most patients, however, relapse after approximately one year due to acquired resistance, and there are currently no second-line options for these resistant patients other than standard chemotherapy. Here, we propose methods to discover molecular mechanisms underlying acquired resistance to crizotinib. We will generate laboratory models of ALK-positive NSCLC from patients with the disease. Models that are not already resistant will be made resistant in the laboratory using methodology that we previously used to identify clinically validated mechanisms of EGFR TKI resistance. We will systematically assess each model for the presence of resistance mutations within ALK itself, for activation of alternative growth pathways that allow cells to bypass ALK, and for defects in the cell death machinery. We will also take more unbiased approaches like gene expression profiling and comparative genomic hybridization to discover potentially novel mechanisms of resistance. Based on our findings, we will design and test therapeutic strategies to overcome resistance in vivo. We will also confirm that these resistance mechanisms are clinically relevant by evaluating resistant tumor specimens from patients. Taken together, these studies will enable the rational selection of subsequent, or second-line, treatments for patients who relapse on crizotinib based on the identified mechanism of resistance. These basic studies will therefore translate into new therapeutic approaches in the clinic that provide long lasting and meaningful benefit to our patients. Lung cancer is the leading cause of cancer-related deaths. For some patients, the ALK targeted therapy crizotinib is highly effective, but remissions are short-lived. Here, we will determine how ALK-positive cancers become resistant to crizotinib in order to develop new treatments that will improve the lives of patients
Keywords: Adenocarcinoma; Affect; anaplastic lymphoma kinase; Applications Grants; base; Biological Models; biomarker; Biopsy; Bypass; Cancer cell line; Cancer Etiology; Cancer Patient; Cell Cycle Arrest; Cell Death; cell growth; Cell Line; Cell Survival; Cells; Cessation of life; chemotherapy; Chromosomal Rearrangement; Clinic; Clinical; clinical infrastructure; clinical remission; Clinical Trials; clinically relevant; combinatorial; Combined Modality Therapy; comparative genomic hybridization; Coupled; Data; Defect; design; Development; Disease; Disease remission; DNA Sequence Rearrangement; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Future; Gatekeeping; Gefitinib; Gene Expression Profiling; genome-wide; Genotype; Goals; Growth; improved; In Vitro; in vivo; Institution; Institutional Review Boards; kinase inhibitor; Laboratories; Laboratory Study; Life; Malignant neoplasm of lung; Malignant Neoplasms; Malignant Pleural Effusion; Mediating; Methodology; Methods; Modeling; Molecular; Molecular Target; mutant; Mutation; Non-Small-Cell Lung Carcinoma; novel; novel therapeutic intervention; Oncogenes; Operative Surgical Procedures; Pathway interactions; Patients; Phase I Clinical Trials; Protein Tyrosine Kinase; Protocols documentation; Relapse; repository; Research Infrastructure; Resistance; Resistance development; resistance mechanism; resistance mutation; response; Sampling; Seminal; Signal Pathway; Smoker; Specimen; subcutaneous; Testing; Therapeutic; Translating; tumor; tumor xenograft; Tyrosine Kinase Inhibitor; United States; Xenograft Model
Relevance: Lung cancer is the leading cause of cancer-related deaths. For some patients, the ALK targeted therapy crizotinib is highly effective, but remissions are short-lived. Here, we will determine how ALK-positive cancers become resistant to crizotinib in order to develop new treatments that will improve the lives of patients
Project start date: 2012-02-20
Project end date: 2016-12-31
Budget start date: 20-FEB-2012
Budget end date: 31-DEC-2012
1R01CA164273-01 (2012): $340686
INFLUENCE OF URINARY MACROMOLECULES ON CRYSTAL AGGREGATION
A Jeffrey, Associate Professor
Medical College Of Wisconsincity: Milwaukee country: United States (us)
Grant 5R01DK082550-03 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Most kidney stones form as aggregates of calcium oxalate monohydrate (COM) crystals under the influence of urinary macromolecules, but currently, no urine test can prospectively identify stone formers. Prior work in our laboratory has shown that the urinary macromolecular mixtures from stone formers have low net negative charge, compared to normal healthy adults. Also, it has been shown that macromolecular aggregation occurs when the net charge is near zero; either by mixing equal protions of polycations and polyanions or by reducing the number of negative charges per chain on polyanions, such as Tamm-Horsfall Protein, and that macromolecular aggregate formation causes COM crystal aggregation. This proposal tests the hypothesis that stone formers can be identified by the presence of low net negative charge in their urinary macromolecules, and that this condition is linked to macromolecular aggregation, crystal aggregation, and stone formation. This proposal will test this hypothesis by following a research protocol with 2 Specific Aims (1) Verification of low net negative charge in urinary macromolecules as the disease marker for stone formers, and correlation with phenotype. Urinary macromolecules from recurrent COM stone formers and normal controls will be isolated and characterized for their net negative charge by Colloidal Titration to verify that low net negative charge is a marker for stone disease, and confirm a simplified sample handling procedure recently developed in our laboratory. These same samples will also be fully characterized with respect to their effect on COM crystal nucleation, aggregation, and growth to define phenotypic cohorts; subsets of patients that are likely to share a common defect in their urinary macromolecules to facilitate identification under Specific Aim 2. Familial cohorts will also be studied for this purpose, since they are likely characterized by a single defect. (2) Identification of the macromolecular structural defect(s) associated with low net negative charge and stone formation. Specific macromolecular components (or combinations thereof) responsible for specific functional defects will be identified in stone formers using various techniques of proteomic analyses, specifically 2 dimensional gel electrophoresis methods and MALDI-TOF mass spectrometry. These methods will identify whether the low net negative charge observed in the urinary macromolecular mixtures of stone formers derives from 1) the presence of additonal polycationic macromolecules, 2) the absence of critical polyanionic macromolecules, or 3) reduction of net charge on critical polyanion macromolecules compared to those in the urine from normal healthy adults, and therefore identify the cause(s) of disease. We anticipate that more than one type of defect will be found, since many different macromolecules are associated with kidney stones. The successful completion of this proposal will yield a diagnostic method, specifically Colloidal Titration, for prospectively identifying stone formers, and allowing for dietary and lifestyle counselling to prevent or delay onset of disease. Identification of altered protein structures leading to the changes observed in the Colloidal Titration assay will help to confirm our model of the stone forming processes, providing the basis for the intelligent design of new therapeutic agents that truly prevent disease recurrence, rather than reduce it, as in current treatments
Keywords: Adult; Agreement; base; Biological Assay; Calcium Oxalate; Calcium Oxalate Monohydrate; Calculi; Characteristics; Charge; Chemicals; cohort; Counseling; Crystal Formation; Crystallization; Defect; design; Development; Diagnostic Procedure; Disease; Disease Marker; Electrophoresis, Gel, Two-Dimensional; Event; Exhibits; Family member; Funding; General Population; Genes; Genetic; glycosylation; Growth; Health; human UMOD protein; In Vitro; Inheritance Patterns; Kidney Calculi; Laboratories; Lead; Life Style; Link; macromolecule; MALDI-TOF Mass Spectrometry; Mass Spectrum Analysis; Measures; Methods; Modeling; Molecular Structure; Nature; novel therapeutics; Onset of illness; Pathway interactions; Patients; Phase; Phenotype; Play; polyanion; polycation; Population; Post-Translational Protein Processing; prevent; Procedures; Process; Promotor (Genetics); protein structure; Proteins; Proteomics; Protocols documentation; Publications; Recurrence; Regulation; Research; Risk; Role; Sampling; Screening procedure; Site; Techniques; Testing; Therapeutic Agents; Titrations; urinary; Urine; Work
Relevance: The successful completion of this proposal will yield a diagnostic method, specifically Colloidal Titration, for prospectively identifying stone formers, and allowing for dietary and lifestyle counselling to prevent or delay onset of disease. Identification of altered protein structures leading to the changes observed in the Colloidal Titration assay will help to confirm our model of the stone forming processes, providing the basis for the intelligent design of new therapeutic agents that truly prevent disease recurrence, rather than reduce it, as in current treatments
Project start date: 2009-08-17
Project end date: 2013-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-07-070
5R01DK082550-03 (2011): $188017
MODEL-BASED IMAGE RECONSTRUCTION FOR X-RAY CT IN LUNG IMAGING
A Jeffrey, Professor
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 5R01HL098686-02 from National Heart, Lung, And Blood Institute
Abstract: Model-Based Image Reconstruction for X-ray CT in Lung Imaging Modern X-ray computed tomography (CT) systems provide high-quality images for diagnosing numerous conditions including a variety of lung diseases. Unfortunately, technological advances in CT imaging have been accompanied by significant increases in X-ray radiation dose to patients. There is growing concern about the public health consequences of such doses. Furthermore, even with typical levels of radiation dose, current X-ray CT images have suboptimal image quality due to the limitations of the traditional image reconstruction algorithms used in clinical systems. We propose to develop, implement, analyze and evaluate model-based image reconstruction (MBIR) methods for X-ray CT to improve image quality in lung imaging and to reduce patient dose. Unlike commercially available denoising methods, the proposed MBIR methods are based on accurate models for the physics and statistics of X-ray CT systems. The methods will use edge-preserving regularization that is tailored to lung scans to control noise while improving spatial resolution. We will develop techniques for accelerating the iterative algorithms used in MBIR methods. The methods will be evaluated using computer simulations, phantom studies, and human studies. Specifically, we will focus here on lung CT applications, including morphological characterization of lung nodules and assessment of pulmonary diseases. The clinical impact of MBIR methods will be studied using automated lung image analysis tools and radiologist observer studies. The relevance of this research to public health is that we will develop and evaluate sophisticated techniques for processing the raw data measured by X-ray CT scanners to dramatically reduce the X-ray radiation dose to patients and to further improve the image quality in lung CT imaging for more accurate diagnosis and treatment
Keywords: Acceleration; Address; Algorithms; Architecture; base; Behavior; Benchmarking; Blinded; Clinical; Computer Simulation; Computers; Data; design; Diagnosis; Diagnostic; Disease; Dose; Drug Formulations; Electronics; Equilibrium; Evaluation; Feedback; Goals; Human; Image; Image Analysis; Image Reconstructions; improved; Lung; Lung diseases; lung imaging; Lung nodule; Mammary Gland Parenchyma; Maps; Measurement; Measures; Memory; Methods; Metric; Modeling; Morphologic artifacts; Motion; Nodule; Noise; novel; Patients; Pattern; Performance; Photons; physical model; Physics; Process; public health medicine (field); public health relevance; quantum; Radiation; radiologist; Ramp; reconstruction; Relative (related person); Research; Resolution; Roentgen Rays; Scanning; shared memory; simulation; Source; Spiral Computed Tomography; Statistical Models; statistics; stem; System; Techniques; Time; Tomography, Computed, Scanners; tool; Tube; Update; Width; X-Ray Computed Tomography; X-Ray Computed Tomography Scanners
Relevance: Narrative The relevance of this research to public health is that we will develop and evaluate sophisticated techniques for process- ing the raw data measured by X-ray CT scanners to dramatically reduce the X-ray radiation dose to patients and to further improve the image quality in lung CT imaging for more accurate diagnosis and treatment
Project start date: 2010-08-01
Project end date: 2013-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-07-070
5R01HL098686-02 (2011): $589088
IMPULSIVE AGGRESSION, NEUROCOGNITION, AND SUICIDAL BEHAVIOR IN DEPRESSED YOUTH
A Jeffrey, Investigator
Research Inst Nationwide Children´s Hospcity: Columbus country: United States (us)
Grant 1R01MH093552-01 from National Institute Of Mental Health
Abstract: Major Depressive Disorder (MDD) is the most potent psychiatric risk factor for suicidal behavior in adolescents, yet most depressed youth never attempt suicide, diminishing the positive predictive value of a diagnosis of MDD in gauging the risk of future suicidal acts. Efforts to prevent youth suicide would benefit greatly from a deeper understanding of precursors and pathways to suicidal behavior in depressed youth, particularly if such knowledge informs the development of effective risk evaluation and intervention strategies. Knowledge of measurable factors that increase the risk of future suicide attempts in depressed adolescents could prove critical to efforts to prevent youth suicide by virtue of 1) aiding in the recognition of depressed youth at especially heightened risk for suicide, who at a minimum may require closer supervision and containment; 2) identifying targets for clinical intervention beyond the mood disorder per se; and, 3) contributing to the development of assessment tools and risk markers relevant to better gauging individual suicide risk and informing clinical intervention research with youth at risk for suicide. The proposed R01 application from an early stage investigator (ESI) will address critical gaps in knowledge by examining the role of impulsive aggression and neurocognitive functioning in the etiopathogenesis of suicidal behavior in adolescents with MDD. The central hypothesis is that impulsive aggression and deficits in executive function and decision making will contribute substantially to a model of future suicide attempts and add positive predictive value to traditional assessment approaches. Our hypothesis is informed by promising pilot work in which measures of impulsive aggression and decision making deficits sharply distinguished depressed adolescent suicide attempters from non-attempters. The design includes cross-sectional comparisons as well as a prospective longitudinal study of 300 depressed youth with and without a prior history of suicide attempt, followed from early to middle adolescence, the developmental period of highest risk for suicidal behavior. These results will contribute to the mission of the NIMH by improving our capacity to identify the temporal and likely causal sequence of antecedents to future suicidal acts in youth with MDD, thus framing targets for practical clinical risk assessment, intervention, and the prevention of suicidal behavior. The severe consequences of adolescent suicidal behavior make the accurate identification of youth at high risk an important clinical, research, and public health objective. This is the first large-scale prospective study of the developmental antecedents of adolescent suicidal behavior to comprehensively address multiple risk and protective factors in depressed youth. With the use of a multi-method, state-of-the-art, and pilot tested approach for assessing impulsive aggression and an informative computerized battery of subtests of executive function and decision making, the proposed research may help to clarify the specific behavioral and neurocognitive pathways contributing to the etiopathogenesis of suicidal behavior. Thus, this work has the potential to inform the development of practical suicide risk evaluation tools, empirically-based treatments, and preventive interventions to reduce adolescent suicide
Keywords: Address; Adolescence; Adolescent; Adolescent Psychiatry; Aggressive behavior; Algorithms; American; Area; Award; base; Behavioral; Brain; Child Psychiatry; Clinical; Clinical Research; Cognitive deficits; computerized; Containment; Coupled; Decision Making; Depressed mood; design; Development; developmental psychology; Diagnosis; Early identification; Environmental Risk Factor; Epidemiology; Evaluation; executive function; family genetics; Foundations; Frustration; Functional disorder; Future; Goals; high risk; Hostility; Impairment; improved; Individual; innovation; Intervention; Intervention Studies; Investigation; Knowledge; longitudinal design; Longitudinal Studies; Major Depressive Disorder; Measurable; Measures; Methods; Mission; Modeling; Mood Disorders; National Institute of Mental Health (U.S.); Neurocognition; Neurocognitive; Neurocognitive Deficit; Neuropsychology; Outcome; Pathway interactions; Play; Predictive Value; prevent; Preventive Intervention; prospective; Prospective Studies; psychosocial; public health medicine (field); Recording of previous events; reducing suicide; Research; Research Personnel; Risk; Risk Assessment; Risk Factors; Risk Marker; Role; Staging; Statistical Methods; statistics; suicidal; suicidal act; suicidal behavior; suicidal risk; Suicide; Suicide attempt; suicide attempter; Suicide prevention; Supervision; Testing; tool; treatment strategy; Work; Youth
Relevance: The severe consequences of adolescent suicidal behavior make the accurate identification of youth at high risk an important clinical, research, and public health objective. This is the first large-scale prospective study of the developmental antecedents of adolescent suicidal behavior to comprehensively address multiple risk and protective factors in depressed youth. With the use of a multi-method, state-of-the-art, and pilot tested approach for assessing impulsive aggression and an informative computerized battery of subtests of executive function and decision making, the proposed research may help to clarify the specific behavioral and neurocognitive pathways contributing to the etiopathogenesis of suicidal behavior. Thus, this work has the potential to inform the development of practical suicide risk evaluation tools, empirically-based treatments, and preventive interventions to reduce adolescent suicide
Project start date: 2011-07-01
Project end date: 2016-04-30
Budget start date: 1-JUL-2011
Budget end date: 30-APR-2012
PFA/PA: PA-10-067
1R01MH093552-01 (2011): $428376
ORIGINS OF ELASTICITY AND VISCOELASTICITY IN LIGAMENTS
A Jeffrey, Associate Professor
University Of Utahcity: Salt Lake City country: United States (us)
Grant 5R01AR047369-11 from National Institute Of Arthritis And Musculoskeletal And Skin Diseases
Abstract: Ligaments are short bands of fibrous connective tissue that guide normal joint motion and restrict abnormal joint movement. Excessive stretching or disruption can result in gross joint instability causing altered joint kinematics, load distribution and increased vulnerability to injury of other ligaments and musculoskeletal tissues. Although the injury and healing of ligaments have been topics of extensive study, fundamental information about the relationship between the ultrastructure of the tissue, structural components of the extracellular matrix and the continuum-level material behavior is severely lacking. The overall aim of this Bioengineering Research Grant focuses on elucidating the individual function and interaction between structural components of the extracellular matrix of ligaments across physical scales. The research specifically focuses on the small leucine-rich proteoglycans (decorin and biglycan), elastin and the multiscale material properties of ligaments. The hypotheses to be addressed are 1) Decorin and biglycan modulate the material properties of connective tissues containing Type I collagen by regulating the assembly and organization of collagen fibrils; 2) Elastin contributes to the multiscale mechanical integrity of ligament by directly resisting applied forces and stabilizing collagen crimp in intact tissue and isolated fascicles; 3) The volumetric material behavior of ligament varies between structural levels, is nonlinear, time-dependent and intrinsically coupled to the uniaxial viscoelastic behavior. Elastin modulates the Poisson´s ratio by coupling fibers and fascicle between structural levels; 4A) A continuum based hyperelastic strain energy that models nonlinear volumetric behavior and the time/rate dependent material behavior with poroviscoelasticity can both describe and predict the experimental results in Aim 3; 4B) The deviatoric and volumetric elastic material behavior of intact ligament and fascicles can be described and predicted by a multi-scale elastic micromechanical model with helical fiber structure and an explicit representation of the elastin network. These hypotheses will be addressed through a series of aims that combine experimental measurements from the molecular level to the continuum level. By integrating molecular, structural and compositional characteristics of ligament into structural mechanical models at different levels, results of this study will have important implications for understanding the fundamental role of the small proteoglycans, elastin and fluid flow in the material behavior of fibrous connective tissues. This will aid the interpretation of the phenotypes associated with disease states that are related to alterations in expression of the small proteoglycans and elastin. The micromechanical model will provide a framework to interpret the mechanical effects of alterations to components of the ground substance and structural organization that occur due to growth, aging and different disease states, and can guide the design of engineered biomaterials. The results of this research will elucidate the mechanistic function of the ground substance components as they relate to the hierarchical structure of ligaments and tendons. The micromechanical model will provide a framework to interpret the mechanical effects of alterations to components of the ground substance and structural organization that occur due to growth, aging and different disease states, and can guide the design of engineered biomaterials
Keywords: Address; aggrecan; Aging; base; Behavior; biglycan; Biocompatible Materials; Biomedical Engineering; Characteristics; Code; Collagen; Collagen Fibril; Collagen Type I; Connective Tissue; Coupled; Coupling; Data; decorin; Degenerative polyarthritis; Digestion; Disease; Elastases; Elasticity; Elastin; Elements; engineering design; Extracellular Matrix; Fascicle; Fiber; fluid flow; Funding; Gel; Ground Substance; Growth; Healed; healing; Individual; Injury; Investigation; Joint Instability; joint mobilization; Joints; kinematics; Leucine; Ligaments; Measurement; Measures; Mechanics; Microscopy; Modeling; Molecular; Motion; Musculoskeletal; Non-linear Models; Phenotype; Property; Proteoglycan; public health relevance; Relaxation; Research; Research Project Grants; research study; Role; Series; Stress; Stretching; Structure; Tendon structure; Testing; Time; Tissues; versican; viscoelasticity; Weight; Weight-Bearing state
Relevance: Relevance The results of this research will elucidate the mechanistic function of the ground substance components as they relate to the hierarchical structure of ligaments and tendons. The micromechanical model will provide a framework to interpret the mechanical effects of alterations to components of the ground substance and structural organization that occur due to growth, aging and different disease states, and can guide the design of engineered biomaterials
Project start date: 2000-09-01
Project end date: 2015-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-10-009
5R01AR047369-11 (2011): $322920
Sponsored Links Excellgen http://Excellgen.com
DAVID W. SMITH WORKSHOP ON MALFORMATIONS AND MORPHOGENESIS
A Jeffrey, Associate Professor
Childrens Hospital Of Philadelphiacity: Philadelphia country: United States (us)
Grant 5R13HD048170-08 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: For the past 29 years the David W. Smith Workshop on Malformations and Morphogenesis has brought together a mix of dysmorphologists, embryologists, anatomists, geneticists, and others who work on developing a better understanding of how human malformations occur and the underlying mechanisms of morphogenesis. The workshops are held annually and were initiated in celebration of the career of Dr. David W. Smith, who was the father of human clinical dysmorphology and first initiated these meetings. Workshops are held over approximately five days, typically on an academic campus in the summer, and have an attendance of 120 to 140 individuals who are selected following submissions of s and reviewed by the scientific program committee. The workshop is intended to provide an interactive exchange and thus is limited only to those presenting that year. Approximately every five years the meetings have been held internationally, but most meetings took place in the United States. Each year three to five central topics are selected by the organizers; which takes into account when the topic had last been a focus, timeliness based on new scientific developments, and new fields. The meetings consist of a workshop format in which short presentations of hypothesis-driven findings are then followed by an intense discussion period. The meetings have a long history of wide-ranging and stimulating discussion, and have provided an especially important focus for the development and recruitment of fellows as well as junior faculty into the field of malformation and morphogenesis. This application is a request to provide continuing support for the David W. Smith Workshop in the form of travel stipends for fellows, junior faculty, and a select number of plenary speakers. This Workshop has a history for being the primary forum where clinicians and basic scientists exchange information on the pathogenesis of human malformations
Keywords: ing; Accounting; base; career; Clinical; Development; Dysmorphology; Educational workshop; Faculty; Fathers; Human; Individual; malformation; meetings; Morphogenesis; Pathogenesis; programs; public health relevance; Recording of previous events; Scientist; Travel; United States; Work
Relevance: This proposal is a request to provide continuing support for the David W. Smith Workshop in the form of travel stipends for fellows, junior faculty, and a select number of plenary speakers. This Workshop has a history for being the primary forum where clinicians and basic scientists exchange information on the pathogenesis of human malformations
Project start date: 2004-08-01
Project end date: 2014-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-08-149
5R13HD048170-08 (2011): $25000
THE INFLUENCE OF DIET AND LIFESTYLE ON PATIENTS WITH ADVANCED COLORECTAL CANCER
A Jeffrey, Assistant Professor Of Medicine
Dana-farber Cancer Institutecity: Boston country: United States (us)
Grant 5R01CA149222-02 from National Cancer Institute
Abstract: Epidemiologic and scientific research indicates that diet and other lifestyle factors have a significant influence on the risk of developing colorectal cancer. Emerging data suggest some of these factors impact on the outcomes of patients with early stage colon cancer. However, there are no data on the influence of diet, lifestyle and other host factors on the outcomes of patients with more advanced colorectal cancer. At the time of initial diagnosis, 20% of colorectal cancer patients have evidence of metastases and another 15- 20% will recur with metastatic disease within a few years of initial diagnosis. In the past 10 years, there have been substantial improvements in chemotherapy options for these patients, with median survival exceeding 2 years and increasing number of patients living 4 or more years. Patients often seek to understand what, if any, diet and lifestyle will improve their outcomes, both survival and tolerability of therapy. Moreover, how diet and lifestyle influence prognosis may depend, in part, on molecular characteristics of the tumor. In response to a NIH Program Announcement, PA-09-148, "Studies of Energy Balance and Cancer in Humans," we propose to address these gaps in knowledge by utilizing data from 2 National Cancer Institute-sponsored chemotherapy trials in newly diagnosed patients with stage IV colorectal cancer (CALGB 80203 and 80405) which provide a) prospective assessments of diet, medication, lifestyle and comorbidities; b) paraffin-embedded tumor specimens to examine how such factors interact with specific molecular alterations; c) blood samples for research purposes; and d) comprehensive data on cancer progression, mortality, and chemotherapy-related toxicity. Since stage, performance status, use of combination chemotherapy and follow-up were carefully defined in this trial, residual confounding by disease characteristics and use of chemotherapy should be minimized. This database will provide the unique opportunity to examine the influence of energy balance (Aim 1), diet and vitamin D (Aim 2) and aspirin/NSAIDs (Aim 3) on the outcomes of patients with advanced colorectal cancer. Beyond the aforementioned hypotheses, this cohort will allow for the rapid examination of future hypotheses as they emerge. Ultimately, this database will permit us to ascertain the influence of numerous factors on colorectal cancer survival, improve our understanding of colorectal cancer biology, and potentially offer substantive diet and lifestyle recommendations for patients and health care providers. Patients with cancer often seek information of diet and lifestyle as part of their therapy. Data generated from this application will help understand whether such factors influence the outcomes of patients. These data may influence treatment recommendations to future patients or lead to the development of a randomized trial to further knowledge in this area
Keywords: Address; adiponectin; angiogenesis; Area; Aspirin; bevacizumab; Blood specimen; Body mass index; C-Peptide; Cancer and Leukemia Group B; Cancer Biology; Cancer Patient; Cardiovascular system; celecoxib; Cetuximab; Characteristics; chemotherapy; cohort; Colon Carcinoma; Colorectal Cancer; Combination Drug Therapy; Comorbidity; cyclooxygenase 2; Data; Databases; density; Development; Diagnosis; Diet; Dietary Intervention; Disease; disease characteristic; energy balance; Epidemiology; Epidermal Growth Factor Receptor; experience; follow-up; Future; Glycemic Index; Health Personnel; Human; improved; indexing; Insulin; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Integration Host Factors; Knowledge; Lead; Leptin; Life; Life Style; lifestyle factors; lifestyle intervention; Malignant Neoplasms; metastatic colorectal; Molecular; Mortality Vital Statistics; Mutate; National Cancer Institute; Neoplasm Metastasis; Newly Diagnosed; NIH Program Announcements; Non-Steroidal Anti-Inflammatory Agents; Obesity; Outcome; outcome forecast; overexpression; Paraffin Embedding; Pathway interactions; Patients; Pattern; Performance Status; Pharmaceutical Preparations; Physical activity; Plasma; pre-clinical; prevent; prospective; Proteins; Proto-Oncogene Proteins c-akt; public health relevance; randomized trial; Recommendation; Research; Residual state; response; Risk; Specimen; Staging; Time; Toxic effect; tumor; tumor growth; tumor progression; Vitamin D; Vitamin D3 Receptor
Project start date: 2010-07-01
Project end date: 2015-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-09-148
5R01CA149222-02 (2011): $506666
PARENTING, SIBLING-SUPPORT, AND INFANT DEVELOPMENT
A Jeffrey
University Of Nebraska Omahacity: Omaha country: United States (us)
Grant 5R01HD042882-07 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: Early environments that developing organisms encounter during ontogeny have profound and persistent effects throughout life. In human offspring, variation in early family environments and gestational endocrine environments can profoundly shape multiple biosocial parameters, including sociality and behavior, stress reactivity, pubertal timing, and later parental style. We will examine the impact of early environments on development in a marmoset model that is relevant to human development. Marmoset development occurs in a family system, with multiple caregivers providing qualitatively and quantitatively different forms of care. Further, mothers often conceive immediately postpartum, leading to elevated maternal steroid hormones (including androgens) that can impact both developing fetuses (via placental transfer) and nursing offspring (via milk-borne steroids), a condition often found in human females (e.g., polycystic ovarian syndrome). In addition, female marmosets also exhibit elevated and varying levels of glucocorticoid hormones during pregnancy, suggesting that offspring may be differentially affected. The studies described in this application will address 3 aims 1) Does variation in early care produce phenotypic variation in behavioral, physiological, and parental care?; 2) How is behavioral, somatic, and reproductive development shaped by pre- and postnatal exogenous steroids in marmosets?; and 3) does variation in gestational exposure to glucocorticoid hormone alter developmental trajectories, particularly in the stress system and somatic development? Using an established colony of marmosets, we will evaluate the links between early care received by marmosets and later parental care toward their own offspring. Secondly, we will look for associations among maternal androgens during gestation and during lactation (including concentrations in milk) and subsequent biobehavioral parameters. Finally, we will monitor cortisol responses to a standardized psychosocial stressor to evaluate whether exposure to high fetal glucocorticoids programs marmosets to be stress-responsive. Differences in early uterine and postnatal social environments predispose developing offspring toward characteristics that have health relevance (e.g., pubertal timing, stress reactivity, sociality). These projects will assess the impact of early environments on biosocial development in marmosets, a species with many similarities to human sociality and biology
Keywords: Address; Adolescent; Adult; Affect; Androgens; Anxiety; Behavior; behavior influence; Behavioral; biobehavior; Biology; Biosocial; Breeding; Callithrix; Caregivers; caregiving; Caring; Characteristics; Complex; Conceptions; Data; Development; Developmental Process; Discipline of Nursing; Endocrine; Environment; Epigenetic Process; Event; Exhibits; experience; Exposure to; Family; Fathers; Female; fetal; Fetal development of the mammalian embryo or fetus; Fetus; Genetic; Glucocorticoids; Growth; Health; Hormones; Human; Human Development; human female; Hydrocortisone; in utero; Individual; Individual Differences; Infant; Infant Development; Lactation; Life; Link; Metabolic; Milk; Modeling; Monitor; Monkeys; Mothers; Nature; Neurosecretory Systems; offspring; Organism; Ovarian; Ovulation; Pair Bond; Parenting behavior; Perinatal; Phenotype; Physiological; Physiological Processes; placental transfer; postnatal; Postpartum Period; Pregnancy; pregnant; prenatal; Primates; Process; programs; psychosocial; pubertal timing; public health relevance; Quality of Care; relating to nervous system; reproductive development; Research; response; Shapes; Siblings; social; Social Development; Social Environment; Source; steroid hormone; Steroids; Stress; stressor; Study Subject; Syndrome; System; Time; transmission process; Twin Multiple Birth; Variant
Relevance: Lay Differences in early uterine and postnatal social environments predispose developing offspring toward characteristics that have health relevance (e.g., pubertal timing, stress reactivity, sociality). These projects will assess the impact of early environments on biosocial development in marmosets, a species with many similarities to human sociality and biology.)
Project start date: 2002-07-01
Project end date: 2015-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-07-070
5R01HD042882-07 (2011): $191100
THE ROLE OF ARX IN NORMAL AND ABNORMAL BRAIN DEVELOPMENT
A Jeffrey, Associate Professor
Childrens Hospital Of Philadelphiacity: Philadelphia country: United States (us)
Grant 5R01NS046616-07 from National Institute Of Neurological Disorders And Stroke
Abstract: Developmental anomalies of the brain, including mental retardation and malformations, occur in approximately 2% of all live born children and epilepsy in about 0.5%, placing them among the most common known childhood disorders. Despite this high frequency, the molecular and cellular basis for only a very few disorders has been recently elucidated, while the basis of many more remains unknown. Mutations in the transcription factor ARX have been described in several children with early childhood epilepsy and mental retardation, both with and without associated brain malformations. As predicted in our first application, mutations of this gene prove to be a relatively common cause of mental retardation and infantile epilepsy based on the wide spectrum of severity already apparent in this group of children and a recurrent mechanism for mutation in at least two of the four polyalanine tracts found in the gene. The developmental mechanism by which ARX mutations result in this wide spectrum of problems is incompletely understood, although emerging data implicate disturbances in radial and nonradial cell migration, two pathways required for normal brain development. Based on data generated from this grant in humans and mice, the following hypotheses have been generated (1) the type of ARX mutation predicts the phenotype in both hemizygous males and heterozygous females; (2) the phenotype in affected female humans and mice correlates with X-inactivation; and (3) Arx with an expanded poly-A tract results in defects in transcriptional repression, ultimate resulting in mice with seizures and mental retardation. To test these hypotheses, a series of experiments are proposed that will discover the mutation types in a large series of male and female patients with candidate phenotypes and determine X-inactivation status. In this application we will focus on elucidating the mechanism of a poly-A tract mutation in causing the neurologic phenotype, and in further understanding the downstream targets of Arx and their role in normal and abnormal brain development and function. The phenotypes in humans and mutant mice with different ARX/Arx mutations will be analyzed and compared to each other and to overlapping phenotypes caused by mutations of related genes. These studies are expected to provide a greater understanding of how Arx functions in normal and abnormal development, and will contribute to our understanding of the pathogenesis of such common disorders in children as mental retardation, epilepsy, and structural anomalies of the brain. Epilepsy and mental retardation co-exist in many children and together extract a significant financial burden on the US health care dollar, an estimated $51.2 billion (in 2003 dollars). Although 3-5% of all children in the United States exhibit epilepsy and/or mental retardation, the underlying pathogeneses for these disorders is poorly understood in most cases. The data from our previous work and from that proposed in this application seeks to understand how one gene, ARX, commonly causes childhood epilepsy and mental retardation. Ultimately we expect these studies will lead to improvements in their diagnosis, treatment, and prevention of these and related neurologic disorders
Keywords: Affect; autism spectrum disorder; base; Binding (Molecular Function); boys; Brain; brain malformation; C-terminal; Cell Death; cell motility; Child; Childhood; cohort; Corpus Callosum; Cryptogenic West Syndrome; Data; Defect; Development; developmental disease/disorder; Diagnosis; Disease; DNA; Dyskinetic syndrome; early childhood; Encephalopathies; Epilepsy; Exhibits; Female; Frequencies (time pattern); Functional disorder; Gene Expression; Gene Mutation; gene repression; Gene Targeting; Genes; Genitalia; Grant; Health; Healthcare; Heterozygote; Homeobox; Homeobox Genes; homeodomain; Human; human female; in vivo; infancy; Infantile spasms; interest; Interneurons; Involuntary Movements; Knock-in Mouse; Lead; Life; Link; lissencephaly; loss of function; male; malformation; Mental Retardation; Methylation; Missense Mutation; Molecular; Mus; Mutant Strains Mice; Mutation; Mutation Analysis; neocortical; nervous system disorder; Neurologic; Neurons; Nuclear Inclusion; Pathogenesis; Pathway interactions; Patients; Phenocopy; Phenotype; Poly A; polyalanine; Prevention; protein folding; Proteins; Radial; Recurrence; research study; Role; Seizures; Series; Severities; sex; Site; Structure; Syndrome; Testing; transcription factor; United States; Variant; Ventricular; Work; X Inactivation
Relevance: Epilepsy and mental retardation co-exist in many children and together extract a significant financial burden on the US health care dollar, an estimated $51.2 billion (in 2003 dollars). Although 3-5% of all children in the United States exhibit epilepsy and/or mental retardation, the underlying pathogeneses for these disorders is poorly understood in most cases. The data from our previous work and from that proposed in this application seeks to understand how one gene, ARX, commonly causes childhood epilepsy and mental retardation. Ultimately we expect these studies will lead to improvements in their diagnosis, treatment, and prevention of these and related neurologic disorders
Project start date: 2003-07-01
Project end date: 2014-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R01NS046616-07 (2011): $461674
TRIAL OF MESNA TO PREVENT DOXORUBICIN-INDUCED PLASMA PROTEIN OXIDATION AND TNFA R
A Jeffrey, Professor
University Of Kentuckycity: Lexington country: United States (us)
Grant 5R01CA153227-02 from National Cancer Institute
Abstract: Cognitive dysfunction after cancer chemotherapy, or ´chemobrain´, occurs after anthracycline- containing regimens. Since anthracyclines, such as doxorubicin, do not enter the central nervous system, the mechanism behind this debilitating sequela of therapy has remained obscure. In contrast, cardiomyopathy is a well-established toxicity of doxorubicin therapy. We propose two paradigm- shifting hypotheses to 1) explain the cognitive and cardiac toxicities of anthracycline chemotherapy, and 2) to propose a remedy. In animal models, doxorubicin-induced CNS and cardiac damage can be reversed with anti-TNF-1 antibody and with the antioxidant 3-GCEE. In an initial clinical study, we observed a significant decrease in oxidative modification of plasma proteins after doxorubicin administration in children who were coincidentally receiving mesna, a drug closely related to 3-GCEE, compared to children who were not coincidentally receiving mesna. Mesna has an extracellular mechanism of action, and is frequently given in combination chemotherapy regimens to prevent hemorrhagic cystitis associated with the alkylating agents ifosfamide and high-dose cyclophosphamide, and is commonly coincidentally co-administered with anthracyclines without affecting cancer therapy outcomes. One of the plasma proteins oxidized by doxorubicin in these patients was APOA1. In further animal studies, we found that mesna abrogates doxorubicin-induced oxidative modification of plasma proteins and prevents induction of stress markers in heart and brain tissues, and in further in vitro studies we have shown that reduced APOA1 inhibits LPS-induced TNF- 1 release from the J774.4 macrophage cell line, while oxidized APOPA1 activates LPS-induced TNF- 1 release from the J774.4 cells. Therefore, we hypothesize mesna will prevent doxorubicin-induced oxidative modification of plasma proteins, including APOA1, and thus prevent TNF-1 production. We will test this hypothesis in a blinded prospective clinical trial. Eligible participants will be cancer patients with breast cancer scheduled to receive the standard regimen A/C (doxorubicin and cyclophosphamide) and non-Hodgkin lymphoma patients scheduled to receive doxorubicin in CHOP or R-CHOP regimens. Participants will receive one cycle with mesna 360 mg/m2 and another cycle with saline prior to and 3 hours after doxorubicin. The primary endpoint will be determination of difference in oxidation of plasma proteins and TNF-1 levels at 6 hours post doxorubicin between the mesna-containing cycles and the saline-containing cycles. If our initial findings are confirmed in this pilot trial, 1) plasma protein oxidation will be established as a novel mechanism of toxicity, 2) a hitherto unknown drug interaction between doxorubicin and mesna will be established, and 3) a larger randomized trial would be justified to study mesna to prevent the sequelae of doxorubicin therapy. Cancer patients receiving chemotherapy regimens that include the anthracycline drugs such as doxorubicin are at risk for developing cognitive and cardiac impairment. We propose a novel hypothesis that these side effects are due to direct oxidative damage of plasma proteins by doxorubicin, and we have demonstrated in an animal model that the drug mesna, which is used to prevent other complications of other chemotherapy drugs, prevents doxorubicin-induced plasma protein oxidative damage and the subsequent induction of markers of neurologic and cardiac injury. Goal This clinical study will determine whether mesna prevents doxorubicin-induced damage of plasma proteins in cancer patients, and will establish plasma protein oxidation as a potential mechanism of anthracycline-induced cognitive and cardiac dysfunction
Keywords: Adverse effects; Affect; Alkylating Agents; Animal Model; Animals; Anthracyclines; Antibodies; Antineoplastic Agents; Antioxidants; Back; Blinded; Blood; Blood - brain barrier anatomy; Brain Injuries; brain tissue; Cancer Patient; cancer therapy; Cardiac; Cardiomyopathies; Cardiotoxicity; Cell Line; Cells; chemobrain; chemotherapy; Chemotherapy-Oncologic Procedure; Child; Clinic; Clinical Research; Clinical Trials; Cognitive; Cyclophosphamide; Cystitis; Dose; Doxorubicin; Drug Interactions; Effectiveness; eligible participant; extracellular; Functional disorder; Goals; Heart; Hematopoietic; Hour; Ifosfamide; Impaired cognition; Impairment; In Vitro; Injury; Intravenous; macrophage; malignant breast neoplasm; Mediating; Mesna; Modeling; Modification; Moscow; Mus; Myopathy; Neuraxis; Neurologic; Non-Hodgkin`s Lymphoma; novel; oxidation; oxidative damage; Participant; Patient Schedules; Patients; Pharmaceutical Preparations; pilot trial; Plasma Proteins; prevent; Principal Investigator; Production; programs; prospective; Proteins; Proteomics; public health relevance; randomized trial; Reactive Oxygen Species; Regimen; Risk; Saline; Schedule; Series; Stress; Syndrome; Testing; therapy outcome; Tissues; TNF gene; Toxic effect; Treatment Protocols
Project start date: 2010-08-01
Project end date: 2013-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: RFA-GM-10-009
5R01CA153227-02 (2011): $269005
THE ROLE OF PI3-KINASE SIGNALING PATHWAY IN DEFINING SENSITIVITY AND RESISTANCE
A Jeffrey, Assistant Professor Of Medicine
Dana-farber Cancer Institutecity: Boston country: United States (us)
Abstract: Clinical studies indicate that a humanized monoclonal antibody against the Epidermal Growth Factor Receptor (EGFR), cetuximab, confers an objective tumor response in a subset of patients with metastatic colorectal cancer. However, most patients do not respond to cetuximab and therefore receive limited or no benefit from this drug. Currently, there is no test that can predict if a cancer will respond to cetuximab. Compelling evidence supports the view that targeting the receptor tyrosine kinases (RTK), particularly those that engage the Phosphoinositide 3-Kinase (PI3K) signaling pathways, is a highly effective strategy for killing for cancers. Accordingly, the therapeutic response to anti-RTK therapy has been shown to be modulated dramatically by the mutational status of key signaling components in the PI3K pathway. The PI3K/Akt signaling pathway drives many epithelial cancers, and its importance in colorectal cancers is underscored by the presence of PIK3CA mutations (the gene encoding for PI3K) in 20-30% of these cancers. PI3K can be activated by multiple different signaling pathways including EGFR, and there is accumulating evidence that EGFR regulates PI3K via distinct mechanisms in cancers sensitive to anti-EGFR therapies. We propose to study the PI3K signaling pathway, biochemically and genetically, in colorectal cancers with the translationa) goal of identifying markers that will predict sensitivity to cetuximab. This will enable the selection of patients that are most likely to benefit from cetuximab. Additionally, these studies may also reveal additional therapeutic targets to enhance cetuximab sensitivity. Our specific aims include (1) Identify the mechanisms for activating the PI3K/AKT pathway in colorectal cancers; (2) To determine the differences in PI3K regulation between cetuximab sensitive and resistant colorectal cancers in xenograft tumor models; (3) To determine if we can use the information discovered in the first two aims to identify markers that will predict which colorectal cancers will respond to cetuximab. Brief Summary Cetuximab, a monoclonal antibody against the Epidermal Growth Factor Receptor, is commonly used to treat patients with metastatic colorectal cancer. However, not all patients benefit from this therapy and currently there are no reliable molecular markers to select patients that will benefit. The goal of this project is to find such markers that can be used to select patients most likely to respond to cetuximab
Keywords: 1-Phosphatidylinositol 3-Kinase; Antibodies; Apoptosis; Archives; base; Binding Proteins; Bioinformatics; Biopsy Specimen; Cancer cell line; cancer genetics; Cancer Patient; caspase-3; Catalytic Domain; cell growth; Cell Line; Cell Survival; Cetuximab; Characteristics; Clinical Research; Clinical Trials; Colon Carcinoma; Colorectal Cancer; comparative genomic hybridization; Dana-Farber Cancer Institute; Dose; Drug Combinations; Enzymes; Epidermal Growth Factor Receptor; Epithelial; Excision; Gene Expression Profile; Gene Mutation; Genes; Genetic; Genetic Transcription; Genomics; Goals; humanized monoclonal antibodies; Immunoprecipitation; indexing; insight; Killings; kinase inhibitor; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of lung; Malignant Neoplasms; Mass Spectrum Analysis; Measures; metastatic colorectal; Modeling; molecular marker; Molecular Profiling; Monoclonal Antibodies; Mus; Mutate; Mutation; Nude Mice; Paraffin; Paraffin Embedding; Pathway interactions; Patient Selection; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Phosphatidylinositols; Phosphotransferases; PIK3CA gene; preclinical study; Proteins; Proto-Oncogene Proteins c-akt; receptor; Receptor Protein-Tyrosine Kinases; Regulation; Resistance; Resources; response; Role; Sampling; Signal Pathway; Signal Transduction; Signaling Protein; Specimen; Testing; Therapeutic; therapeutic target; Time; Tissues; tumor; Tumor Bank; tumor xenograft; Tyrosine; Western Blotting; Xenograft procedure
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5P50CA127003-05_0004 (2011): $364242
NOVEL COMPOUNDS TO INACTIVATE ONCOGENIC FUSION PROTEINS
A Jeffrey
Georgetown Universitycity: Washington country: United States (us)
Grant 5R01CA133662-03 from National Cancer Institute
Abstract: Chemotherapy-resistant leukemias and sarcomas contain tumor-specific chromosomal translocations that encode fusion-proteins and these fusion-proteins are expressed only in the tumor. A fusion-protein provides significant tumor target specificity and increases the likelihood that novel therapies targeting the fusion-protein will be both effective and lack non-specific toxicity. Many of the tumor-specific fusion-proteins that function as transcription factors are disordered proteins. Disordered proteins lack the rigid alpha-helical or beta sheet structures required for structure-based drug design. While disordered proteins require a more empiric approach to the discovery of small molecule protein-protein interaction inhibitors, the biochemical properties of disordered proteins may actually favor the success of protein-protein interaction inhibitors. We will develop a novel paradigm to inhibit the protein-protein interaction of an oncogenic fusion protein. The Ewing´s Sarcoma Family of Tumors (ESFT) contains a characteristic translocation, t(1122), which leads to the oncogenic, fusion-protein, transcription factor EWS-FLI1. Therapies that inactivate EWS-FLI1 might address the significant problem of recurrent disease for patients. Since EWS-FLI1 lacks intrinsic enzymatic activity, and is a disordered protein, we will create novel protein-protein interaction inhibitors to block EWS-FLI1 binding to critical protein partners. We identified RNA Helicase A (RHA, p150), a DEAD/H family member that modulates gene expression, as a critical partner of EWS-FLI1. EWS-FLI1 binds to a unique region of RHA that is NOT involved in non-malignant RHA transcriptional modulation. A peptide mimic of this binding region inhibits EWS- FLI1 binding to RHA and we have discovered a lead compound, NSC635437, which has significant structural homology with the peptide mimic. A derivative small molecule of NSC635437, YK-4-279, blocks RHA binding to EWS-FLI1 and induces apoptosis in ESFT cells. We hypothesize that the interaction of RHA with EWS- FLI1 results in a potent transcriptional activator/coactivator complex, which amplifies the functions of both proteins and drives the malignant phenotype of ESFT. Our approach will develop reagents that prevent the binding of EWS-FLI1 to RHA, both to address our hypothesis and create a new therapeutic agent. We will accomplish our objectives by examining the effects of blocking RHA from enhancing EWS-FLI1 function, first using a peptide and then with small molecule protein-protein interaction inhibitors. We will work together with Dr. Milton Brown, a highly regarded medicinal chemist, to chemically optimize our lead compound. Our work has broad applicability to a larger group of tumors, serving as a new paradigm for developmental therapeutics. This paradigm to create small molecule inhibitors of EWS-FLI1 could be used for other translocation-defined malignancies such as chemotherapy-resistant carcinomas, sarcomas and leukemias. Therefore, future work would have a strong potential for a positive impact upon many patients with difficult to treat tumors leading to reduced mortality and morbidity. New targeted therapies are needed for cancer patients that improve survival and decrease side-effects of therapy. Ewing´s Sarcoma Family of Tumors (ESFT) are highly malignant tumors of bone and soft tissue that occur in children, adolescents, and young adults. The tumors often grow in close proximity to bone, but can occur as a soft-tissue mass. Current standard therapy for ESFT patients is a five-drug regimen that lasts for approximately 9 months. Patients who present with localized ESFT have approximately 70% disease-free survival. Patients who present with metastatic ESFT have a poor prognosis (20% disease-free survival) despite intensive therapy. These clinical response rates have persisted for the past decade, even after dose-intensifying chemotherapy and bone marrow transplantation. Therefore, we need to discover novel therapeutic approaches to both reduce treatment related morbidity and improve overall survival. Fortunately, ESFT contain an ideal molecular target. Unfortunately, despite knowledge that inactivation of this ideal target causes ESFT cell death, strategies to inactivate the molecular target have not been brought to the clinic. This project will specifically address the need for new targeted therapies for ESFT and a large number of related malignancies that have chromosomal translocations
Keywords: 0-11 years old; 3-D; 3-Dimensional; Address; Adolescent; Adolescent Youth; adult youth; Adverse effects; Amino Acids; aminoacid; Apoptosis; Apoptosis Pathway; Assay; Au element; base; beta pleated sheet; Beta Sheet; Binding; Binding (Molecular Function); Bioassay; Biochemical; Biochemistry; Biologic Assays; Biological Assay; Blood (Leukemia); bone; Bone; Bone and Bones; Bone Marrow Transplant; Bone Marrow Transplantation; Bone Tissue; Bones and Bone Tissue; Cancer Genes; Cancer of Bone; Cancer of Prostate; Cancer Patient; Cancer-Promoting Gene; Cancers; Carcinoma; cDNA Arrays; cDNA Microarray; cell biology; Cell Death; Cell Death, Programmed; cell growth; Cell Line; Cell Lines, Strains; Cell Locomotion; Cell Migration; cell motility; Cell Movement; CellLine; Cells; Cellular biology; Cellular Expansion; Cellular Growth; Cellular Migration; Characteristics; Chemistry, Biological; Chemistry, Pharmaceutical; chemotherapy; Child; Child Youth; children; Children (0-21); Chimera Protein; Chimeric Proteins; ChIP (chromatin immunoprecipitation); CHIP assay; chromatin immunoprecipitation; Chromosomal dislocation; Chromosomal translocation; chromosome dislocation; chromosome translocation; Clinic; Clinical; Complex; Connective Tissue Sarcoma; cultured cell line; design; designing; Developmental Therapeutics; Developmental Therapeutics Program; Developmental Therapy; Disease; Disease-Free Survival; disease/disorder; Disorder; DNA Molecular Biology; Dose; Drug Design; drug discovery; drug/agent; Drugs; DTP; epithelial carcinoma; Epithelial Neoplasms, Malignant; Epithelial Tumors, Malignant; Event-Free Survival; Ewing Sarcoma Breakpoint Region 2; Ewing`s Family of Tumours; Ewing`s Sarcoma/Peripheral Primitive Neuroectodermal Tumor; Ewing`s Tumor; Ewings sarcoma; EWS-FLI-1; EWS-FLI1; EWS-FLI1 fusion protein; EWSR2; experiment; experimental research; experimental study; Expression Profiling; Expression Signature; Family; Family member; FLI1; FLI1 gene; Forecast of outcome; Fusion Protein; Future; Gene Expression; gene product; Gene Transcription; Generalized Growth; Genetic Transcription; Gold; Grafting, Bone Marrow; Growth; Health; heavy metal lead; heavy metal Pb; Heterograft; Human, Child; improved; inhibitor; inhibitor/antagonist; Investigation; juvenile; juvenile human; Killings; Knowledge; Lead; leukemia; Leukemias, General; Libraries; malignancy; Malignant Bone Neoplasm; Malignant neoplasm of prostate; Malignant Neoplasms; Malignant Osseous Neoplasm; Malignant Osseous Tumor; malignant phenotype; Malignant prostatic tumor; Malignant Soft Tissue Neoplasm; Malignant Tumor; Malignant Tumor of the Bone; Malignant Tumor of the Prostate; Malignant Tumor of the Soft Tissue; Marrow Transplantation; Math Models; mathematical model; mathematical modeling; Medication; Medicinal Chemistry; Metastatic Ewing`s Sarcoma; molecuar profile; Molecular Biology; Molecular Fingerprinting; Molecular Interaction; Molecular Profiling; molecular signature; Molecular Target; Morbidity; Morbidity - disease rate; Mortality; Mortality Vital Statistics; Motility; Motility, Cellular; necrocytosis; neoplasm/cancer; neoplastic cell; new therapeutics; next generation therapeutics; Non-Malignant; nonmalignant; novel; novel therapeutic intervention; novel therapeutics; oncogene protein pp60(v-src) (137-157); Oncogenes; Oncogenic; ontogeny; Osseous Cancer; outcome forecast; Patients; Pb element; peptide A; Peptides; Pharmaceutic Chemistry; Pharmaceutic Preparations; Pharmaceutical Chemistry; Pharmaceutical Preparations; prevent; preventing; Prognosis; Property; Property, LOINC Axis 2; Prostate CA; Prostate Cancer; Prostatic Cancer; protein function; protein protein interaction; Proteins; Reagent; Recurrent disease; Regimen; Relapsed Disease; Reporter; Research; research study; Resistance; resistant; response; RHA enzyme; RNA Expression; RNA helicase A; sarcoma; Sarcoma of the Soft Tissue and Bone; Sarcoma, Soft Tissue; screening; Screening procedure; screenings; Series; SIC-1; side effect; small molecule; soft tissue; Specificity; Structure; success; Targeted Fusion Protein Therapy; Testing; Therapeutic Agents; therapy adverse effect; Tissue Growth; Toxic effect; Toxicities; Transcription; Transcription Activator; Transcription Coactivator; transcription factor; Transcription Factor Coactivator; Transcription, Genetic; Transcriptional Activator; Transcriptional Activator/Coactivator; Transcriptional Coactivator; Transforming Genes; Translocation, Genetic; Transplantation, Heterologous; treatment adverse effect; Treatment Side Effects; tumor; Tumor Cell; tumor growth; Work; Xenograft; Xenograft Model; Xenograft procedure; Xenotransplantation; young adult; youngster
Relevance: New targeted therapies are needed for cancer patients that improve survival and decrease side-effects of therapy. Ewing´s Sarcoma Family of Tumors (ESFT) are highly malignant tumors of bone and soft tissue that occur in children, adolescents, and young adults. The tumors often grow in close proximity to bone, but can occur as a soft-tissue mass. Current standard therapy for ESFT patients is a five-drug regimen that lasts for approximately 9 months. Patients who present with localized ESFT have approximately 70% disease-free survival. Patients who present with metastatic ESFT have a poor prognosis (20% disease- free survival) despite intensive therapy. These clinical response rates have persisted for the past decade, even after dose-intensifying chemotherapy and bone marrow transplantation. Therefore, we need to discover novel therapeutic approaches to both reduce treatment related morbidity and improve overall survival. Fortunately, ESFT contain an ideal molecular target. Unfortunately, despite knowledge that inactivation of this ideal target causes ESFT cell death, strategies to inactivate the molecular target have not been brought to the clinic. This project will specifically address the need for new targeted therapies for ESFT and a large number of related malignancies that have chromosomal translocations
Project start date: 2009-01-01
Project end date: 2013-11-30
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-07-070
5R01CA133662-03 (2011): $286661
A Jeffrey, Professor And Director
Medical College Of Wisconsincity: Milwaukee country: United States (us)
Abstract: CAIR´s Administration Core is responsible for overall planning, budgetary, and management oversight of the Center. Under the reorganization planned forthe renewal period, the Center´s scientific leadership, planning, and decision-making body will be its Executive Committee, composed of ail Core Directors and an investigator who is elected annually by all fulltime faculty. The Executive Committee¿chaired by the Center´s Associate Director¿will oversee CAIR´s new Centerwide Initiative Development Workgroup process to ensure shared, integrated decision-making in the Center´s scientific, development, training, advisory committee, and evaluation activities. The Administration Core will support these Executive Committee functions. In addition, the Core manages administrative aspects ofthe Center, interacts with the parent institution in matters pertaining to administration and planning, and maintains budgetary oversight of CAIR. The Administration Core also provides centralized support to Center investigators with respect to personnel management, grant application preparation, and human subjects/IRB materials
Keywords: Acquired Immunodeficiency Syndrome; Advisory Committees; Applications Grants; Appointment; Budgets; career; Communities; Decision Making; Development; Ensure; Evaluation; Faculty; human subject; Institution; Institutional Review Boards; Intervention Studies; investigator training; Leadership; Manuscripts; Mentorship; Parents; Performance; Personnel Management; Preparation; Process; Productivity; Reporting; Research; Research Personnel; Resources; Training
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
5P30MH052776-18_7042 (2011): $438091
GENETICALLY ENGINEERED ANTIGEN SPECIFIC TREG TO TREAT AUTOIMMUNITY
A Jeffrey, Professor
University Of California San Franciscocity: San Francisco country: United States (us)
Abstract: Autoimmunity is reaching epidemic proportions with tens of millions of people suffering from diseases such as multiple sclerosis, rheumatoid arthritis, type 1 diabetes (T1D), systemic lupus erythematosus and others. In addition to its financial costs, the long term complications of these diseases can be devastating. A curative therapy is desperately needed. At present, efforts to prevent or reverse autoimmune diseases have been limited by the lack of safe and effective immunotherapies. With this challenge in mind, we believe the induction of immunological tolerance is a fundamental requirement for any effective therapy. Previous studies, including numerous published reports from our ACEs group and others, have focused on the use of regulatory T cells (Tregs) as one means of restoring tolerance in autoimmunity. This notion is based on the core "principle that treatment with Tregs will lead to the induction of long-term tolerance. Most significantly, there is strong evidence that self-antigen-specific Tregs are most effective to treat a variety of autoimmune diseases. However, the identification and application of these cells have been compromised by the lack of effective isolation and expansion protocols for these low frequency cells. Thus, novel approaches are necessary to address this need. Specifically, this application proposes to develop novel approaches to generate a sufficient quantity of antigen-specific Tregs capable of restoring tolerance and averting autoimmunity. These studies will be performed as a collaborative effort between the Abbas and Bluestone labs where multiple mouse models have been established and be used to rapidly test theoretical cell manipulations. These efforts will inform and enhance the bulk research efforts in his proposal develoted to human Treg studies and the development of engenerred Tregs that can be used both to study the biology of Tregs and potentially be developed for clinical application. To address these key issues, the following specific aims are proposed. Aim 1.Develop engineered antigen-specific Tregs by introducing autoreactive T cell receptors (TCRs) and other therapeutic genes. Aim 2. Assess the mechanisms and safety of cellular therapy with engineered Tregs. Aim 3. To generate high numbers of autoreactive engineered Tregs capable of suppressing pathogenic autoreactive T cell responses
Keywords: Address; Affect; Antigens; Autoantigens; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Autologous; autoreactive T cell; B-Lymphocytes; base; Biology; Cell physiology; Cell Therapy; Cells; Chronic; clinical application; design; Development; Disease; effective therapy; Engineering; Epidemic; Financial cost; Frequencies (time pattern); Future; Generations; Genes; Genetic Engineering; Goals; Human; Human Engineering; Immune response; Immune system; Immunotherapy; In Vitro; in vivo; in vivo Model; Inbred NOD Mice; Insulin; Insulin-Dependent Diabetes Mellitus; islet; Lead; Longevity; Measures; migration; Mind; mouse model; Multiple Sclerosis; Mus; Natural immunosuppression; novel; novel strategies; Pancreas; Patients; Population; prevent; Prevention; Proinsulin; Protocols documentation; Publishing; Regulatory T-Lymphocyte; Reporting; Research; research study; restoration; Rheumatoid Arthritis; Safety; Specificity; success; Suicide; Systemic Lupus Erythematosus; T cell response; T-Cell Immunologic Specificity; T-Cell Receptor; T-Lymphocyte; Techniques; Testing; therapeutic gene; Viral; Work
Relevance: The ability to manipulate the immune system through re-establishing tolerance is a highly relevant goal to the treatment of autoimmune diseases. Cell-based therapies can provide a novel approach if we can develop a highly antigen-specific, stable autologous regulatory T cell population that can be administered in sufficient numbers. Success in the aims outlined in this project will move this field forward in clincally relevant ways
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
5U19AI056388-08_7493 (2011): $197234
ASSESSING DEVELOPMENT TRAJECTORIES OF THE BRAIN BIOCHEMISTRY IN ADHD AT 4 TESLA
A Jeffrey
Wayne State Universitycity: Detroit country: United States (us)
Grant 5R01MH065420-06 from National Institute Of Mental Health
Abstract: Attention Deficit Hyperactivity Disorder (ADHD) is a serious public health problem that affects between 3 to 9% of children and accounts for between 30 to 40% of child referrals to mental health services. While the pathogenesis of this illness remains poorly understood, ADHD is increasingly seen as a neurodevelopmental disorder implicating inhibitory regulation, executive function, motivational processes, perception and motor control. Our long-term goal is to increase our understanding of neurodevelopmental deviations in pediatric ADHD. The objective of this renewal application is to test whether alterations of the earlier developing striatum precede alterations that occur later in the slower developing prefrontal areas such as the dorsolateral prefrontal cortex (DLPFC). From childhood to adolescence, the brain undergoes substantive structural and functional changes with differential timing, which parallel the maturation of cognition and behavior. This process of "fine-tuning" or maturing cognitive performance includes the elimination of overproduced neuronal connections or synapses, which can be assessed using the noninvasive neuroimaging method, in vivo phosphorous (31P) spectroscopy. From our first-cycle of funding, the cross-sectional in vivo 31P spectroscopy results acquired at 1.5 Tesla show basal ganglia deficits suggesting an underdevelopment of dendritic branching and synaptic formations, and prefrontal cortex deficits but only in the relatively older ADHD children suggesting an underachieved maturational process of fine-tuning. However, to definitively assess developmental changes over time requires longitudinal measurements. Therefore, the aims of this study are to acquire longitudinal whole-brain 3D multi- voxel 31P spectroscopy and ultra-high resolution anatomical MRI measurements at 4 Tesla in children and adolescent with and without ADHD; that is baseline plus two follow-up visits 12-months apart. Using a high- field MR system dramatically improves the regional specificity and biochemical resolution. Deviations in cortical surface topography will be assessed as well as neuropsychological measures targeting different cognitive/behavioral domains will be collected at each time point. The overall hypothesis of this longitudinal study is that children with ADHD will demonstrate regional deviations in neurodevelopmental trajectories relative to healthy controls including in the slower developing DLPFC, but not until the onset of the fine-tuning processes in the DLPFC that occurs late in childhood. Significance If confirmed, these studies will provide more direct evidence of a developmental mechanism targeting a bottom-up dysfunction in the striatum potentially impairing the fine-tuning of control processes or executive functions in the prefrontal cortex of children with ADHD. Additionally, these observations will establish a foundation of biochemical trajectories in pediatric ADHD contrasted against healthy controls, which may lead toward improved assessment and treatment of ADHD. PUBLIC HEALTH RELEVANCE Attention Deficit Hyperactivity Disorder (ADHD) is a serious public health problem that affects between 3 to 9% of children and accounts for between 30 to 40% of child referrals to mental health services. While the cause of this illness remains poorly understood, ADHD is increasingly seen as a neurodevelopmental disorder. This work promises to identify where in the brain and at what age certain alterations occur in children and adolescents with ADHD, and this information of changes with age can then potentially be used as a predictor of treatment outcome.
Keywords: 0-11 years old; 11 year old; 12-20 years old; 14 year old; Accounting; Active Follow-up; AD/HD; Address; ADHD; Adolescence; adolescence (12-20); Adolescent; Adolescent Youth; Affect; Age; age group; Age Group Unspecified; Aminoethanols; Anterior; Area; Attention; attention deficit hyperactive disorder; Attention deficit hyperactivity disorder; Attention-Deficit Disorder, Predominantly Hyperactive-Impulsive Type; Basal Ganglia; Basal Nuclei; base; Behavior; Behavioral; Bilateral; Biochemical; Biochemistry; Brain; Brain region; Chemistry, Biological; Child; Child Youth; Childhood; children; Children (0-21); Choline Chloride Dihydrogen Phosphate; Choline Phosphate; Choline Phosphate Chloride; Cognition; Cognitive; Corpus Striatum; Corpus striatum structure; Data; Dendrites; Development; Dorsal; Dysfunction; eleven year old; Encephalon; Encephalons; Ethanaminium, N, N, N-trimethyl-2-(phosphonooxy)-, chloride; ethanolamine phosphate; Ethanolamines; executive control; executive function; experiment; experimental research; experimental study; follow-up; Foundations; fourteen year old; Frequencies (time pattern); Frequency; Functional disorder; Funding; Gender; Generalized Growth; Goals; gray matter; Growth; heavy metal lead; heavy metal Pb; Human, Child; Hyperactivity Disorder NOS; Hyperactivity Disorder, Predominantly Hyperactive-Impulsive Type; Hyperkinetic Syndrome; Image; imaging; improved; in vivo; juvenile; juvenile human; Lead; Left; long-term study; Longitudinal Studies; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Magnetic Resonance Spectroscopy; Measurement; Measures; Medial; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Membrane; membrane structure; Memory, Immediate; Memory, Short-Term; Memory, Shortterm; Mental Health Services; Mental Hygiene Services; Methods; Methods and Techniques; Methods, Other; Modeling; motivational processes; Motor; motor control; MR Imaging; MR Spectroscopy; MR Tomography; MRI; MRS; MRSI; Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; Neural Development; Neurocyte; neurodevelopment; Neurodevelopmental Disorder; neuroimaging; Neurological Development Disorder; neuronal; Neurons; Neuropil; Neuropsychologic Tests; neuropsychological; Neuropsychological Tests; NMR Imaging; NMR Tomography; Nuclear Magnetic Resonance Imaging; ontogeny; Parietal; Pathogenesis; pathophysiology; pathway; Pathway interactions; Pb element; pediatric; Perception; Performance; performance tests; Phosphatides; Phosphocholine; phosphodiester; phosphoethanolamine; Phospholipids; phosphomonoester; Phosphorous; Phosphorylcholine; Phosphorylcholine Chloride; phosphorylethanolamine; Physiopathology; Play; Prefrontal Cortex; Process; Protocol; Protocols documentation; Public Health; public health medicine (field); public health relevance; recruit; Recruitment Activity; Regulation; Relative; Relative (related person); research study; Resolution; Role; Short-Term Memory; social role; Socio-economic status; Socioeconomic Status; Solid; Specificity; Spectroscopy; Spectrum Analyses; Spectrum Analysis; Status, Socioeconomic; striatal; Striate Body; Striatum; substantia alba; substantia grisea; Surface; Synapses; Synaptic; System; System, LOINC Axis 4; Techniques; teenage; Testing; Thick; Thickness; Time; Tissue Growth; Treatment outcome; ultra high resolution; Visit; Weight; white matter; Work; working memory; youngster; Zeugmatography
Relevance: Assessing Developmental Trajectories of the Brain Biochemistry in ADHD at 4 Tesla Stanley, Jeffrey A. Attention Deficit Hyperactivity Disorder (ADHD) is a serious public health problem that affects between 3 to 9% of children and accounts for between 30 to 40% of child referrals to mental health services. While the cause of this illness remains poorly understood, ADHD is increasingly seen as a neurodevelopmental disorder. This work promises to identify where in the brain and at what age certain alterations occur in children and adolescents with ADHD, and this information of changes with age can then potentially be used as a predictor of treatment outcome.
Project start date: 2010-01-15
Project end date: 2014-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-07-070
5R01MH065420-06 (2011): $573131
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