CELL PRIMING, RECEPTOR CROSS-TALK AND ACUTE LUNG INJURY
A Mark
University Of Pittsburgh At Pittsburghcity: Pittsburgh country: United States (us)
Grant 5R01HL079669-07 from National Heart, Lung, And Blood Institute
Abstract: Hemorrhagic shock (HS) resulting from severe trauma promotes the development of systemic inflammatory response syndrome (SIRS) by activating and priming the inflammatory process through as of yet unclear mechanisms. Acute lung injury (ALI) is a major component of SIRS and often serves as a direct cause of death to patients. The lung vascular endothelium is an active organ and plays a central role in the development of ALI through synthesis and release of a number of inflammatory mediators. IL-12 is a key cytokine with multiple effects on lung inflammatory processes. Lung endothelial cells (EC) are one important source of IL-12 in response to HS insult. Conversely, lung EC is targets of IL-12, causing the production of a range of inflammatory molecules, including IL-12 itself, in response to IL-12 stimulation. Thus, lung EC through interacting with IL-12 forms a feedback mechanism to amplify lung inflammation in HS. The production of active IL-12 is tightly controlled by Inflammasome. Despite the central role of IL-12 in the development of SIRS, anti-IL-12 therapy aimed at blocking IL-1 receptor has not been successful. Targeting at inflammasome, however, may present a novel anti-IL-12 strategy for post-trauma SIRS. However, the mechanism underlying HS initiation of inflammasome in the lung and EC is unclear. We have observed two receptor cross-talk mechanisms that might mediate HS activation and priming of inflammasome. We found that TLR4 signaling upregulates type I IL-1 receptor (IL-1RI), and thereby sensitizing the cells to IL-12 stimulation; and HS enhances Toll-like receptor (TLR)4 signaling upregulation of TLR2 in lung EC, which in turn augments IL-12 release in response to TLR2 ligands. In the proposed study we will test the hypotheses that 1) HS through targeting lung EC inflammasome promotes the development of ALI; 2) cross-talk of TLR4- IL-1RI is a novel feedback mechanism amplifying lung inflammation in HS; and 3) cross-talk of TLR4-TLR2 serves as an important mechanism mediating HS-primed inflammasome activation. The burden of disease related to trauma is considerable. Acute lung injury (ALI) is a major component of post- trauma SIRS. However, few specific targets have yet been identified that predispose to SIRS and ALI. Since lung endothelial cells (EC) and IL-12 play important and roles in hemorrhagic shock (HS)-induced inflammation, and inflammasome sits at the center in controlling the IL-12 process, an insight of the mechanisms of HS initiation of EC inflammasome will provide us novel targets for therapeutic interventions of post-HS SIRS and ALI. We propose to study the mechanisms underlying HS-induced lung EC inflammasome activation and priming. In a broader sense, the studies will contribute to a greater understanding of the pathogenesis of a number of human diseases in which EC are involved in the inflammatory process
Keywords: Aftercare; Alveolar Macrophages; base; burden of illness; Cause of Death; Cells; Cessation of life; chemokine receptor; cytokine; Development; Endothelial Cells; Feedback; Grant; Hemorrhagic Shock; human disease; Infection; Inflammation; Inflammation Mediators; Inflammatory; insight; Interleukin-1; Interleukin-12; Ligands; Lung; Lung Inflammation; Lung Injury, Acute; Mediating; Mediator of activation protein; migration; Morbidity - disease rate; Mortality Vital Statistics; neutrophil; novel; novel strategies; Organ; Pathogenesis; Patients; Pattern recognition receptor; Play; Process; Production; public health relevance; receptor; Receptor Cross-Talk; receptor expression; response; Role; Sepsis Syndrome; Signal Transduction; Source; Stimulus; Testing; Therapeutic Intervention; TLR2 gene; TLR4 gene; toll-like receptor 4; Trauma; Up-Regulation (Physiology); Vascular Endothelium
Relevance: The burden of disease related to trauma is considerable. Acute lung injury (ALI) is a major component of post- trauma SIRS. However, few specific targets have yet been identified that predispose to SIRS and ALI. Since lung endothelial cells (EC) and IL-1¿ play important and roles in hemorrhagic shock (HS)-induced inflammation, and inflammasome sits at the center in controlling the IL-1¿ process, an insight of the mechanisms of HS initiation of EC inflammasome will provide us novel targets for therapeutic interventions of post-HS SIRS and ALI. We propose to study the mechanisms underlying HS-induced lung EC inflammasome activation and priming. In a broader sense, the studies will contribute to a greater understanding of the pathogenesis of a number of human diseases in which EC are involved in the inflammatory process
Project start date: 2004-12-01
Project end date: 2015-01-31
Budget start date: 1-FEB-2012
Budget end date: 31-JAN-2013
5R01HL079669-07 (2012): $314500
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to A Mark
DESIGN STUDIES AND OPTIMIZATION OF PHASE-CONTRAST MAMMOGRAPHY
A Mark
Washington Universitycity: Saint Louis country: United States (us)
Grant 7R01EB009715-02 from National Institute Of Biomedical Imaging And Bioengineering
Abstract: X-ray phase-contrast imaging promises to have a major impact on diagnostic radiology, and has reached the point of feasibility for routine clinical use. Because X-ray phase-contrast imaging utilizes a contrast mechanism based on the refractive index values of tissue, it can permit visualization of object features that present little or no absorption contrast. Consequently, phase-contrast mammography can operate effectively at higher X-ray energies than conventional mammography, resulting in a dramatic reduction of the radiation dose, and potentially the ability to improve imaging of dense breasts. The broad objective of this proposal is to develop and evaluate novel system and algorithm designs for phase-contrast mammography. Our research methodology is designed to bring the distinctive features of phase-contrast imaging a step closer to clinical reality. We will investigate the use of a tungsten anode with relatively high kVp values for low-dose phase- contrast mammography. The geometry of the imaging system will be systematically optimized in conjunction with the X-ray source size and spectrum. We will also implement and evaluate non-conventional imaging systems that employ polycapillary optics to collimate the incident X-ray beam, thereby achieving improved beam-coherence properties and decreased image-acquisition times. Finally, robust numerical algorithms will be developed and implemented for reconstructing images that depict the absorption and refractive properties of breast tissue. Experimental studies will be conducted to verify the imaging models that underlie our computer-simulation studies. Task-based measures of image quality derived from numerical observers and human reader studies will guide our optimization studies and ensure that we arrive at clinically meaningful, optimized solutions. Based on the results of our optimization studies, pre-clinical prototype imagers will be constructed and experimentally investigated. Reader studies will be conducted to assess improvement in image quality as compared to standard radiography and establish the groundwork for future clinical translation of the developed imaging technologies. The specific aims of the project are (1) To identify optimal imaging geometries and X-ray source properties for X-ray phase-contrast mammography; (2) To investigate the use of polycapillary optics to improve phase-contrast and reduce image acquisition times; (3) To develop and investigate robust methods for quantitative phase-retrieval; (4) To objectively assess image quality produced by the phase-contrast mammography system designs; and (5) To construct and experimentally evaluate prototype phase-contrast mammography imagers. The development of phase-contrast mammography will yield a powerful and effective new modality for breast cancer imaging. The images it produces will improve a reader´s ability to detect subtle cancer features and it could also dramatically reduce the radiation exposure to the patient
Keywords: absorption; Algorithms; Anodes; Appearance; base; Breast; Breast Microcalcification; cancer imaging; Chicago; Clinical; Clinical Trials; Computational algorithm; Computer Simulation; Coupled; data acquisition; design; Detection; Development; Diagnostic radiologic examination; Doctor of Medicine; Dose; Ensure; Evaluation Methodology; Exposure to; Formalin; Future; Goals; Human; Image; Imagery; Imaging technology; improved; innovation; Investigation; Knowledge; malignant breast neoplasm; Malignant Neoplasms; Mammary Gland Parenchyma; Mammography; Marketing; Measures; member; Methods; Modality; Modeling; Molybdenum; novel; Optics; Patients; Phase; physical property; preclinical study; Property; Protocols documentation; prototype; public health relevance; Radiation; Reader; Refractive Indices; Research Design; Research Methodology; research study; Retrieval; Roentgen Rays; Screening procedure; soft tissue; Solutions; Source; Specimen; Synchrotrons; System; Techniques; technology validation; theories; Time; Tissues; Translations; Tungsten; Universities
Relevance: The development of phase-contrast mammography will yield a powerful and effective new modality for breast cancer imaging. The images it produces will improve a reader´s ability to detect subtle cancer features and it could also dramatically reduce the radiation exposure to the patient
Project start date: 2010-03-15
Project end date: 2013-12-31
Budget start date: 1-JAN-2011
Budget end date: 29-FEB-2012
PFA/PA: PA-07-070
7R01EB009715-02 (2011): $383455
1R01EB009715-01A1 (2010): $483173
REGULATION OF HEPATIC NKT CELLS BY CDLD+ LIVER CELLS
A Mark, Assistant Professor Of Medicin
Beth Israel Deaconess Medical Centercity: Boston country: United States (us)
Grant 5R21CA143748-02 from National Cancer Institute
Abstract: Worldwide, nearly 200 million people have hepatitis C virus (HCV), the great majority of which have chronic hepatitis, nearly 2% in the U.S. are infected with HCV, a major public health challenge with ~9,000 U.S. deaths / yr. currently. Chronic hepatitis frequently leads to cirrhosis, which in turn is the major risk factor for hepatocellular carcinoma (HCC). Although roles of specific immunity in acute and chronic hepatitis C (CHC) are emerging, little is known about key liver immune subset changes with progression. Adaptive HCV-specific T cells are concentrated in liver with innate-like natural killer (NK) and NKT, which represent to ~50% of normal and diseased liver leukocytes. Hepatic NKT are implicated in protection against acute viral infection, but maybe subverted by HCV. Regulation of activation of hepatic NKT cells is poorly understood. This proposal is to determine mechanisms by which the major and heterogeneous population of human hepatic NKT, that we first functionally defined, are regulated by CD1d+ liver cells in hepatitis C. Based on our findings, we hypothesize that in chronic hepatitis C, this large heterogeneous population of liver NKT, instead of being protective, promote inflammation and fibrosis, believed to be prerequisites for development of HCC. We propose that hepatic CD1d can present novel lipid ligands to liver NKT cells. We have evidence for ligand(s) for hepatic NKT and we have isolated fractions from CD1d+ cells that stimulate iNKT selectively. These data provide proof-of-principle that we can obtain fractions with ligand-like activity for NKT. This proposal will exploit our unique expertise with human hepatic and control NKT, physiological CD1d+ presenting liver cells, and reagents we and collaborators have developed to identify hepatic NKT- activating fractions and potential ligands from lipid libraries, to provide target(s) for preclinical development of potential novel therapeutic interventions in CHC and HCC. Given deleterious effects of chronic NKT stimulation we have uncovered, this will enable us to potentially manipulate hepatic NKT through novel molecule(s) toward novel therapeutics to help delay progression to cirrhosis and HCC in hepatitis C. Aim 1. Establish a representative panel of human hepatic CD1d-reactive NKT cells and test candidate small molecules for specific activation or inhibition of hepatic NKT cells vs. blood invariant NKT cells. 1a. Prepare and functionally characterize enriched hepatic NKT panels for use alongside our iNKT. 1b. Determine which iNKT ligands from a selective library also activate hepatic NKT and which inhibit. Aim 2. Determine specificity of human hepatic NKT for hepatic vs. other CD1d+ target cells, and define hepatic CD1d+ cell fractions that specifically activate or inhibit hepatic NKT. 2a. Determine whether enriched hepatic NKT cells have distinct fine specificity for hepatic vs. other CD1d+ target cells relative to iNKT cells. 2b. Identify fractions of eluted liver CD1d ligands that specifically activate hepatic NKT and/or iNKT. Worldwide nearly 200 million people have hepatitis C and many of these will progress to develop complications of the infection, including cirrhosis and hepatocellular carcinoma. This proposal is to study and manipulate a major immune population in the human liver, ´NKT´ cells, which while protective in acute infections appear to contribute to inflammatory and fibrotic damage leading to liver disease progression
Keywords: Acids; Acute; Acute Hepatitis; adaptive immunity; base; Blood; Cell Fraction; Cell-Free System; Cells; cellular targeting; Cessation of life; Chronic; Chronic Hepatitis; Chronic Hepatitis C; Cirrhosis; cytokine; Cytolysis; Data; Development; Disease Progression; Environment; Fibrosis; Gene Expression; Hepatic; Hepatitis C; Hepatitis C virus; Hepatocyte; Human; human tissue; Immune; Immunity; In Vitro; in vivo; Incidence; Infection; Inflammation; Inflammatory; killer T cell; Lead; Leukocytes; Libraries; Ligands; Lipids; Literature; Liver; Liver diseases; Location; Mammals; Natural Killer Cells; novel; novel strategies; novel therapeutic intervention; novel therapeutics; Patients; Physiological; Population; Population Heterogeneity; pre-clinical; Primary carcinoma of the liver cells; public health medicine (field); public health relevance; Reagent; Recombinants; Regulation; Regulatory T-Lymphocyte; Relative (related person); Reporting; response; Risk Factors; Rodent; Role; Screening procedure; small molecule; Specificity; Stimulus; System; T-Lymphocyte; T-Lymphocyte Subsets; Testing; tumor; Tumor Immunity; Viral; Virus Diseases
Relevance: Narrative Worldwide nearly 200 million people have hepatitis C and many of these will progress to develop complications of the infection, including cirrhosis and hepatocellular carcinoma. This proposal is to study and manipulate a major immune population in the human liver, ´NKT´ cells, which while protective in acute infections appear to contribute to inflammatory and fibrotic damage leading to liver disease progression
Project start date: 2010-06-28
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-08-244
5R21CA143748-02 (2011): $183549
LOH AT BRCA1/BRCA2 LOCI IN MUTATION CARRIERS AS A PRECURSOR TO BREAST TUMORIGENES
A Mark, Assistant Professor
Rutgers The St Univ Of Nj New Brunswickcity: New Brunswick country: United States (us)
Grant 5R21CA122795-02 from National Cancer Institute
Abstract: Women who carry mutations in the BRCA1 or BRCA2 tumor suppressor genes are at extreme risk for breast cancer. BRCA1 or BRCA2 mutation carriers are heterozygous, but their breast tumors typically show loss of heterozygosity (LOH), i.e., loss of the wild-type BRCA allele. LOH at the BRCA loci has been thought of as a rare event, occurring in single cells that are the proximate precursors of a tumor. Recent evidence suggests it may occur instead as earlier or more frequent events giving rise to a large population of cells poised for neoplastic transformation - a "field effect". This study will determine whether LOH at the BRCA loci is typically present in histologically normal or pre-neoplastic breast epithelia of mutation carriers. It is a first step in exploring the potential of LOH at the BRCA loci as a marker for diagnosis or prognosis in mutation carriers, and for new approaches to chemotherapy and chemoprevention that target the DNA repair defects of cells lacking BRCA1 or BRCA2 function. Specific aims will be 1. To determine whether LOH at the BRCA loci is typically present in pre-neoplastic and histologically normal tissue outside the margins of breast tumors in mutation carriers. Samples of breast tissue will be micro-dissected and assayed by Pyrosequencing, a high-throughput, micro-sequencing technology for mutation detection and allele quantification. For each patient, an individualized Pyrosequencing assay at the mutation site will be designed for direct quantification of the mutant and wild-type alleles. 2. To determine whether LOH at the BRCA loci can be similarly detected in breast tissue removed in prophylactic mastectomy from BRCA mutation carriers, in advance of any diagnosis of breast cancer. 3. To test the feasibility of detecting LOH at the BRCA loci in breast biopsies of BRCA mutation carriers. This project will study genetic (DNA) changes in women from certain families that are prone to breast cancer. Understanding how these changes take place in breast tissue may open new approaches to early diagnosis, treatment and prevention for this special, high-risk group of patients
Keywords: Abscission; Alleles; Allelic Loss; Allelomorphs; Anti-Oncogenes; Antioncogenes; Assay; Atypical hyperplasia; Bilateral; Bioassay; Biologic Assays; Biological Assay; Biological Preservation; Biopsy; Biopsy, Core Needle; Body Tissues; brca 1 gene; brca 2 gene; BRCA1; BRCA1 gene; BRCA2; BRCA2 gene; BRCA2 Gene Product; BRCA2 Mutation; BRCA2 Protein; Breast; Breast Cancer 1 Gene; Breast Cancer 1, Early Onset Gene; Breast Cancer 2 Gene; Breast Cancer 2 Gene Product; Breast Cancer 2, Early Onset Gene; Breast Cancer 2, Early Onset Protein; breast cancer diagnosis; Breast Cancer Prevention; Breast Cancer Type 1 Susceptibility Gene; Breast Cancer Type 2 Susceptibility Gene; Breast Cancer Type 2 Susceptibility Protein; Breast Lump; Breast Neoplasms; Breast Nodule; Breast Tissue; Breast Tumors; cancer diagnosis; Cancer of Breast; Cancerous; Cancers; Cell Count; Cell Number; Cell Transformation, Neoplastic; Cells; Chemoprevention; chemotherapy; Core Biopsy; Correlative Study; Defect; design; designing; Detection; Development; Diagnosis; DNA Damage; DNA Damage Repair; DNA Injury; DNA Repair; DNA Repair Deficiency; DNA Repair Disorder; drug/agent; Drugs; Ductal; early detection; Early Diagnosis; Emerogenes; Epithelial; Epithelial Cells; Epithelium; Event; Excision; Extirpation; Family; FANCB; FANCD1; Forecast of outcome; Genes, Cancer Suppressor; Genes, Onco-Suppressor; Genetic; Genetic Alteration; Genetic Change; Genetic defect; Genetic Polymorphism; genome mutation; Genome Stability; Hereditary; Hereditary Breast Cancer 1; Hereditary Breast Cancer 2; Heterozygote; high risk; Histologic; Histologically; homologous recombination; Hyperplasia; Hyperplastic; Incidence; Inherited; Laboratories; Lateral; LBUL; Lobule; loss of function; Loss of Heterozygosity; malignancy; malignant breast neoplasm; Malignant neoplasm of breast; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Breast; Mammary Cancer; mammary cancer prevention; Mammary Gland Parenchyma; Mammary Gland Tissue; Mammary Neoplasms; mammary tumor; mammary tumor prevention; Mammectomy; Mass in breast; Mastectomy; Medication; Microdissection; Molecular Marker of Prognosis; mutant; Mutate; Mutation; mutation carrier; Mutation Detection; Mutation of the BRCA2 Gene; neoplasm/cancer; neoplastic; Neoplastic Cell Transformation; neoplastic transformation; new approaches; Normal Tissue; Normal tissue morphology; novel approaches; novel strategies; novel strategy; Oncogenes, Recessive; Oncogenes-Tumor Suppressors; Oncogenesis; oncosuppressor gene; Operation; Operative Procedures; Operative Surgical Procedures; outcome forecast; Palpable; palpable disease; Paraffin Embedding; Patients; peripheral blood; Pharmaceutic Preparations; Pharmaceutical Preparations; polymorphism; Polymorphism (Genetics); Polymorphism, Genetic; Population; preservation; Preservation, Biologic; Preservation, Biological; Prevention; Prognosis; Prognosis Marker; prognostic; Prognostic Marker; prophylactic; protein function; PSCP; public health relevance; Removal; Research; resection; Risk; RNF53; Sampling; Site; Stability, Genomic; surgery; Surgical; Surgical Interventions; Surgical Pathology; Surgical Procedure; Surgical Removal; Technology; Testing; Tissue Sample; Tissues; tumor; Tumor Suppressing Genes; tumor suppressor; Tumor Suppressor Genes; Tumor Suppressor Proteins; Tumor Tissue; tumorigenesis; Unscheduled DNA Synthesis; Woman
Relevance: This project will study genetic (DNA) changes in women from certain families that are prone to breast cancer. Understanding how these changes take place in breast tissue may open new approaches to early diagnosis, treatment and prevention for this special, high-risk group of patients
Project start date: 2009-03-01
Project end date: 2012-02-28
Budget start date: 19-MAY-2010
Budget end date: 28-FEB-2012
PFA/PA: PA-06-299
5R21CA122795-02 (2010): $204375
SEROTONIN GENES & INDIVIDUAL DIFFERENCES IN REWARD VS. PUNISHMENT-BASED LEARNING
A Mark
Rutgers The State Univ Of Nj Newarkcity: Newark country: United States (us)
Grant 5R03MH090307-02 from National Institute Of Mental Health
Abstract: While prior work has suggested that serotonin is involved in modulating tolerance to aversive events, far too little is known about the relationship between serotonin and cognition. Advancing our understanding of the neural and genetic mechanisms through which serotonin influences individual differences in learning to respond to aversive events is a necessary first step towards a deeper understanding of vulnerabilities to mental health disorders such as depression, anxiety, and stress disorders. Toward that end, the primary aim of this project is to study naturally occurring variations in two serotonin genes, how they differentially affect peoples´ biases for learning to obtain reward versus learning to avoid punishment, and how these genetic variations in cognitive styles interact with personality and gender. Because many genes that are implicated in mental disorders also show naturally occurring variations in healthy individuals, understanding the function of these genes is a key component of understanding both individual differences in learning and memory, and how genetic variation can contribute to risk for mental disorders. The proposal represents a new cross-disciplinary collaboration between two established cognitive neuroscientists (the PI, Mark Gluck and the Co-I, Catherine Myers) and two geneticists, Emilia Vitale and Annette Lee, consultants to this grant. The primary cognitive measure used will be a novel probabilistic categorization task developed by the PI, Co-PI and colleagues in which subjects are trained to classify four stimuli into two categories. Because two of the stimuli are trained via positive-rewarding feedback to correct answers and two of the stimuli are trained via negative-punishing feedback to incorrect answers, the task allows for analysis of individual differences in sensitivity to positive versus negative feedback during learning. This task, along with personality assessment tools that measure novelty seeking and harm avoidance, provide a means to test the hypothesis that individuals with a genetic predisposition for reduced levels of serotonin in the brain will be biased to process negative feedback at the expense of positive feedback during such learning tasks. The particular genotypes to be evaluated are (1) a single nucleotide polymorphism, His452Tyr, in the serotonin 2a receptor gene (5-HT2AR) and (2) a 44-nucleotide insertion/deletion in the promoter region of the serotonin transporter gene (5HTTLPR). Individuals with one or both of these less common polymorphisms are predicted to show the highest levels of sensitivity to punishment in learning and highest levels of harm avoidance personality. Building on prior work suggesting that serotonin is involved in modulating tolerance to aversive events, this research will expand our understanding of the neural and genetic bases of individual differences in learning to predict and respond to aversive events. This, in turn, may lead to a deeper understanding of individual differences in vulnerability to mental health disorders such as depression, anxiety, stress disorders, and eating disorders. Better understanding of the function of serotonin function in healthy individuals may also provide insights into why drug efficacy for some of these disorders may vary across individuals
Keywords: Address; Affect; Alleles; Anxiety; Architecture; Area; Award; base; Behavior; Behavior assessment; Behavioral; Behavioral Genetics; Boa; Books; Brain; Brain Injuries; career; Categories; Cognition; Cognitive; cognitive neuroscience; Cognitive Science; Collaborations; computational neuroscience; Data; Data Collection; Decision Making; Dentistry; Disease; Dopamine; drug efficacy; Eating Disorders; Ensure; Environment; Equipment; Event; Faculty; Feedback; Funding; Gender; gene function; Genes; Genetic; genetic analysis; Genetic Materials; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Risk; Genomics; Genotype; Goals; Grant; Guidelines; Hand; Housing; Human; Human Genetics; improved; Impulsivity; Individual; Individual Differences; innovation; insertion/deletion mutation; insight; Institutes; Italy; Lead; Learning; Measures; Medical Research; Medicine; member; Memory; Memory Disorders; Memory Loss; Mental Depression; Mental disorders; Methodology; Methods; Mission; Molecular; National Institute of Drug Abuse; National Institute of Mental Health (U.S.); National Institute of Neurological Disorders and Stroke; National Research Council (U.S.); neuropsychological; Neurosciences; Newsletter; novel; Nucleotides; Other Genetics; Patients; Personality; Personality Assessment; Personality Traits; Pharmaceutical Preparations; Phenotype; Process; professor; programs; Promoter Regions (Genetics); Psychology; public health medicine (field); public health relevance; Publications; Punishment; receptor; Receptor Gene; Receptor, Serotonin, 5-HT2A; relating to nervous system; Relative (related person); Research; Research Ethics Committees; Research Personnel; Research Project Grants; Research Subjects; Resources; Rewards; Risk; Role; Senior Scientist; Serotonin; serotonin transporter; Single Nucleotide Polymorphism; Staging; Stimulus; Testing; Textbooks; tool; Training; trait; Traumatic Stress Disorders; United States National Institutes of Health; Universities; Variant; Variation (Genetics); Work
Relevance: Relevance Building on prior work suggesting that serotonin is involved in modulating tolerance to aversive events, this research will expand our understanding of the neural and genetic bases of individual differences in learning to predict and respond to aversive events. This, in turn, may lead to a deeper understanding of individual differences in vulnerability to mental health disorders such as depression, anxiety, stress disorders, and eating disorders. Better understanding of the function of serotonin function in healthy individuals may also provide insights into why drug efficacy for some of these disorders may vary across individuals
Project start date: 2010-03-18
Project end date: 2012-02-29
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
PFA/PA: PA-09-163
5R03MH090307-02 (2011): $69300
IMMUNE FUNCTION AND THE PROGRESSION TO TYPE 1 DIABETES
A Mark, Eminent Scholar
University Of Floridacity: Gainesville country: United States (us)
Grant 5P01AI042288-14 from National Institute Of Allergy And Infectious Diseases
Abstract: While genetic susceptibility and environment clearly represent realms of influence for the development of type 1 diabetes, a series of immunological abnormalities are inherent to the immune dysregulation that results in the autoimmune destruction of pancreatic (3 cells. Indeed, our previous PO1 studies of individuals with or at increased-risk for type 1 diabetes, as well as in the non-obese diabetic (NOD) mouse model of the disease, associated a series of specialized immune system cells and specific mediators with the disorder. However, issues related to the interplay between these specialized cells and the mediators that allow for abnormal immune regulation, the specificity of these immunological defects in type 1 diabetes versus other autoimmune and metabolic disorders, as well as the ontogeny of immune dysregulation in the natural history of the disease (both prior to and after onset) remain unclear. Our goal in seeking renewal of this P01 grant is to address these outstanding issues; all for the continued purpose of testing our hypothesis that antigen presenting cells (dendritic cells, macrophage/monocytes), through their interaction with components of the cellular immune system (iNKT cells, regulatory T cells), form a critical facet to the immune dysregulation which results in type 1 diabetes. This P01 renewal will examine this hypothesis through three separate but highly interactive Projects. The Projects utilize the NOD mouse model and an extremely valuable population of human subjects with or at increased-risk for type 1 diabetes, as well as healthy controls or persons with type 2 diabetes. The PO1 application is comprised of three Projects Project 1 (S.B. Wilson, PI) - iNKT Cell Gene Expression and Effector Function in Type 1 Diabetes; Project 2 (M. Clare-Salzler, PI) - Interferons alpha/beta in Type 1 Diabetes Pathogenesis; and Project 3 (M. Atkinson, PI) - Immune Regulation and Type 1 Diabetes Pathogenesis. The projects will be supported by two well established Core facilities A-Administration; B-Pathology & Immunology. The successful completion of these P01 studies should prove beneficial to improving our understanding of those events critical to the natural history of type 1 diabetes, identifying markers that enhance our ability to monitor cellular immune activities in the disease, uncovering the interplay between the genetics, environment and the immune response in the pathogenesis of type 1 diabetes, as well as developing immunotherapies capable of preventing or reversing the disorder
Project start date: 1997-09-30
Project end date: 2012-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
5P01AI042288-14 (2011): $1117395
5P01AI042288-13 (2010): $1177132
NATIONAL CENTER FOR BIOMEDICAL ONTOLOGY
A Mark, Professor
Stanford Universitycity: Stanford country: United States (us)
Grant 5U54HG004028-07 from Office Of The Director, National Institutes Of Health
Abstract: We propose to continue the National Center for Biomedical Ontology (NCBO), which develops tools and methods for assimilating, archiving, accessing, and applying machine-processable representations of biomedical domain objects, processes, and relations to assist in the management, integration, visualization, analysis, and interpretation of the huge, distributed data sets that are now the hallmark of biomedical research and clinical care. Our center is truly national in scope, with participation of leading scientific groups at Stanford, Mayo Clinic, University at Buffalo, and the University of Victoria. Our objectives are defined by the following six Cores (1) the development of enhanced computational methods for management of ontologies and controlled terminologies using current Web standards; integration of ontology authoring, publishing, and peer review; creation of a comprehensive ontology-based index of publicly available data resources; development of new analytic methods to summarize and profile biomedical data; (2) the promotion of Driving Biological Projects that can stimulate our research by suggesting new requirements and offering new test beds for deployment-initially involving the Cardiovascular Research Grid, the Rat Genome Database, the caNanoLab nanoparticle database, and the i2b2 National Center for Biomedical Computing, and later engaging the WHO´s development of lCD-11, studies performed by ArrayExpress, and projects that will be selected via open requests for applications; (3) the maintenance of a computational infrastructure to support our research, development, and dissemination activities; provision of user support to the growing number of researchers and clinicians who use our technologies; (4) the training of the next generation of scientists in biomedical ontology; (5) a comprehensive set of dissemination activities, that include workshops, tutorials. Web-based seminars, and a major international conference; and (6) outstanding project administration conducted by a dedicated and talented management team. The NCBO will accelerate the transition of biomedicine into the world of e-science, facilitate the creation of a National Health Information Infrastructure, and extend a network of collaboration through its interactions with other NCBCs, with other research consortia, and with the biomedical community at large
Relevance: RELEVANCE (See instructions): The NCBO supports a burgeoning user community that is using ontologies to enhance biomedical research and to improve patient care. It supports bench scientists, clinician researchers, and workers in informatics in data annnotation, data integration, information retrieval, natural-language processing, electronic patient record systems, and decision-support systems. It is a primary source of semantic-technology infrastructure and expertise for biomedical research and the development of advanced clinical information svstems
Project start date: 2005-09-23
Project end date: 2015-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: RFA-RM-09-002
5U54HG004028-07 (2011): $3617185
IMMUNE REGUALTION AND TYPE 1 DIABETES PATHOGENESIS
A Mark, Eminent Scholar
University Of Floridacity: Gainesville country: United States (us)
Abstract: We and others have recently investigated patients with type 1 diabetes for the frequency and function of a population of regulatory T cells (Treg), characterized by the simultaneous expression of CD4 and CD25. Our studies did not support the notion that altered CD4+CD25+ T cell frequencies are associated with type 1 diabetes, but rather identified type 1 diabetes related alterations in the functional activities of these cells in terms of suppressing effector T (Teff) cell responses in vitro. The need to bring resolution to the aforementioned published discrepancies in frequency and function of Treg in type 1 diabetes, as well as investigate the potential for Teff cell defects, would be afforded with expanded studies that include the parameters of age, metabolic control, and disease duration, as well as to define (in association with Projects 1 and 2) the cellular and molecular mechanism(s) underlying this defect. Therefore, the overall objective of Project 3 is to improve our understanding the mechanisms of immune regulation afforded by CD4+CD25+ T cells, identify their contribution to the pathogenesis of type 1 diabetes, and evaluate the potential of these cells to serve as a marker for autoimmune disease activity. Our specific aims are designed to test the hypothesis that Treg cells are functionally defective in type 1 diabetes, as a result of dysregulated interactions with APC, Teff, and NKT cells, and that the cellular & molecular basis for this defect resides in pathways controlling the phenotypic signature of Treg including surface CD25, FOXP3, as well as TGFfS. This hypothesis has been formed based on our observations of deficient functional activities of Treg in human type 1 diabetes, recent data suggesting the surface expression/stability of CD25 is crucial to maintaining regulatory homeostasis between Treg and Teff, literature indicating the immunological synapse with other immune system cells (e.g., DC, NKT cells) may influence the functional activities of Treg, as well as information suggesting key roles for a limited number of cytokines (e.g., IL-2, IL-10, TGFp) and matrix metalloproteinases are associated with these regulatory processes. The Project has two specific aims 1) Identify the influence of age, type 1 diabetes, and metabolic control on the frequency and function of regulatory T cells defined by co-expression of CD4 and CD25, as well as on the cellular expression of the fork-head transcription factor FoxPS. 2) Define the molecular mechanisms underlying deficiencies in CD4+CD25+ T cell function in subjects with type 1 diabetes. The successful completion of these studies could provide key information to fill an existing knowledge void regarding the mechanistic interactions between specific cell populations that underlie the failure of immune regulation which results in type 1 diabetes
Keywords: Address; Age; Autoimmune Diseases; base; Cell physiology; Cells; cytokine; Data; Defect; design; Development; Diabetes Mellitus; Disease; Eragrostis; Failure (biologic function); Frequencies (time pattern); Goals; Head; Homeostasis; Human; IL2RA gene; illness length; Immune; immune function; Immune system; Immunologic Factors; immunological synapse; Immunologics; improved; In Vitro; Insulin-Dependent Diabetes Mellitus; interest; Interleukin-10; Interleukin-2; Investigation; Knowledge; Literature; Matrix Metalloproteinases; Metabolic Control; Methods; Molecular; Monitor; Pathogenesis; Pathway interactions; Patients; Population; prevent; Process; Publishing; Regulation; Regulatory T-Lymphocyte; Research; Resolution; response; Role; Surface; T-Lymphocyte; Testing; Therapeutic Intervention; Time; tool; transcription factor; Writing
Project start date: 2011-09-01
Project end date: 2012-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
5P01AI042288-14_0009 (2011): $256084
5P01AI042288-13_0009 (2010): $261570
Sponsored Links Excellgen http://Excellgen.com
CLINICAL AND RESEARCH TRAINING PROGRAM FOR ACADEMIC VASCULAR MEDICINE SPECIALISTS
A Mark, Director, Vascular Center
Brigham And Women´s Hospitalcity: Boston country: United States (us)
Grant 5K12HL083786-05 from National Heart, Lung, And Blood Institute
Abstract: Vascular diseases constitute some of the most common causes of disability and death in Western society. Yet, few physicians have chosen vascular disease as an area of clinical specialization. Academically oriented vascular medicine training programs are required to develop vascular medicine specialists with the leadership skills and academic credentials to educate future generations of vascular specialists. Accordingly, we propose to establish a comprehensive Vascular Medicine training program that includes 1) a core clinical curriculum taught by a multidisciplinary faculty of vascular medicine physicians, vascular surgeons and vascular radiologists; 2) an extended didactic clinical research curriculum; and 3) a mentored clinical research experience. The proposed program will admit seven trainees, each for three years. The first year of the program will include clinical training and expose the trainee to all aspects of vascular medicine including peripheral arterial disease, renal and mesenteric vascular disease, cerebrovascular disease, venous thromboembolism, venous insufficiency, lymphedema, vasculitis, vasospasm, and less common vascular disorders. Clinical time will be devoted to inpatient and outpatient vascular consultations, the noninvasive vascular laboratory, computed tomographic and magnetic resonance angiography, peripheral angiography, endovascular interventions and vascular surgery. The second and third years of training will emphasize clinical research. This will include an extended didactic clinical research curriculum emphasizing epidemiology, statistics, clinical trials design, and include principles of pharmacology, genetics in clinical investigation, bioethics and responsible research conduct and additional coursework leading to a Masters degree in Medical Science or Public Health, as appropriate given training and career goals. Coursework will be supplemented by research seminars and journal clubs. Trainees will work closely with mentors who will supervise their research activity and guide the trainees´ career development. The mentored clinical research experience will include a vascular research project and teach skills in protocol development, experimental technique, methods, analysis, oral presentation, manuscript writing and grant preparation. Research activities will leverage the many clinical research programs and facilities that are available at Brigham and Women´s Hospital, Harvard Medical School and the Harvard School of Public Health. These resources will provide significant opportunities for the trainee to acquire clinical research skills and facilitate a successful transition towards independence as a clinical investigator. As a consequence of the intensive clinical and research training integrated in this program, we are confident that we will successfully prepare future academic leaders in the field of Vascular Medicine
Keywords: Angiography; Area; Bioethics; Blood Vessels; career; career development; Cerebrovascular Disorders; Cessation of life; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Clinical Trials Design; Consultations; disability; Educational Curriculum; Educational process of instructing; Epidemiology; experience; Faculty; Future; Future Generations; Genetic; Goals; Grant; Hospitals; Inpatients; Intervention; Journals; Kidney; Laboratories; Leadership; Lymphedema; Magnetic Resonance Angiography; Manuscripts; Master`s Degree; Medical; medical schools; Medicine; Mentors; Mesenteric artery ischemia; Methods; multidisciplinary; Operative Surgical Procedures; Oral; Outpatients; Peripheral; Peripheral arterial disease; Pharmacology; Physicians; Preparation; programs; protocol development; public health medicine (field); Public Health Schools; radiologist; Research; Research Activity; Research Project Grants; Research Training; Resources; responsible research conduct; Science; skills; Societies; Specialist; statistics; Surgeon; Techniques; Thromboembolism; Time; Training; Training Programs; Vascular Diseases; Vasculitis; Vasospasm; Venous; Venous Insufficiency; Woman; Work; Writing
Project start date: 2006-06-01
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: RFA-HL-05-002
5K12HL083786-05 (2011): $862877
5K12HL083786-04 (2009): $991334
BUILDING CAPACITY OF TOBACCO CESSATION IN INDIA & INDONESIA
A Mark
University Of Arizonacity: Tucson country: United States (us)
Grant 5R01TW007944-05 from National Cancer Institute
Abstract: Tobacco cessation is a global health priority not yet addressed in low and low-middle income countries such as India and Indonesia. An important lesson gleaned from international health is that interventions proven effective in western countries cannot simply be exported to developing nations without significant cultural adaptation. Research is urgently needed to find the most effective means of promoting cessation in local contexts. A first step in gaining public attention about the harm of tobacco use and the need for cessation is to involve the medical community in tobacco cessation efforts. It has been well established that before tobacco use declines in the general population, health care providers must be at the forefront of tobacco cessation efforts. To do so, they must quit tobacco use themselves, routinely ask patients about tobacco use, and advise them to quit. At present, there is little involvement of physicians in tobacco cessation efforts in India and Indonesia. Based on four years of experience during Project Quit Tobacco International (QTI) (under the previous Fogarty initiative), the proposed project unfolds as a four-step process to develop a cohort of tobacco cessation researchers in India and Indonesia, using local medical schools as a hub for research activities in both the health care community and the community at large. Medical schools will become centers for recruiting and training tobacco cessation researchers as well as sites for implementing pilot studies and mobilizing local tobacco cessation research networks. The specific objectives of the project are to (1) increase knowledge about the risks of tobacco use and the importance of cessation through dissemination of a model tobacco education curriculum for medical schools in India and Indonesia; (2) recruit and train tobacco researchers concurrently with introducing tobacco education in nine medical schools in each country; (3) involve partner medical schools in tobacco cessation-related community-based research pilot studies, and (4) build capacity in tobacco-related research in both countries by creating tobacco cessation research networks in the six states (three in each country) where project activities will take place. Developed over the past four years, the QTI tobacco cessation research centers in India and Indonesia have begun to engage the communities in which they are located. In-country researchers have gained the skills and confidence to take the next step toward building research capacity beyond their institutions in these two culturally diverse nations. The proposed project will leverage lessons learned during QTI and provide an infrastructure for training a next generation of local tobacco researchers to meet the challenges of tobacco cessation within their own countries
Keywords: Address; Adopted; Asians; Attention; Awareness; base; Cessation Research; Clinic; cohort; Collaborations; Commit; Communities; Community Health; Community Healthcare; Community Practice; Conscious; cost effective; Counseling; Country; Developing Countries; Educational aspects; Educational Curriculum; Environment; experience; Faculty; Fostering; Funding; General Population; Glean; global health; Goals; Government; Health; Health Personnel; Health Priorities; Health Professional; Home environment; Income; India; Indonesia; Institution; Interdisciplinary Study; interest; International; international center; Intervention; Joints; Knowledge; Learning; Locales; Medical; Medical Education; Medical Faculty; medical schools; meetings; member; Mentors; Modeling; Morbidity - disease rate; Mortality Vital Statistics; next generation; Nongovernmental Organizations; Participant; patient population; Patients; Physicians; Pilot Projects; population health; Positioning Attribute; Private Sector; Process; programs; Province; public health medicine (field); Public Sector; Recruitment Activity; Research; Research Activity; Research Design; research in practice; Research Infrastructure; Research Personnel; Research Training; Risk; Services; Site; skills; Students; Sum; Tobacco; tobacco control; Tobacco use; Tobacco Use Cessation; Training; Training Activity; Training and Infrastructure; Women`s Group; Work; Workplace
Project start date: 2007-09-13
Project end date: 2012-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: RFA-TW-06-006
5R01TW007944-05 (2011): $295903
MYOGENIC TONE IN THE URETHRA AND ITS MODULATION
A Mark
Dundalk Institute Of Technologycity: Dundalk country: Ireland (ei)
Grant 5R01DK068565-05 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: This study seeks to explore the cellular mechanisms underlying myogenic tone in the urethra and the means by which these are regulated by neurotransmitters that are known to modulate urethral tone. Our central hypothesis is that specialized pacemaker cells (interstitial cells or IC) produce rhythmic electrical activity similar to that of the interstitial cells of Cajal in the gastrointestinal tract. This in turn is conducted to neighboring smooth muscle cells (SMC) which are recruited to cause a sustained contraction. To test this model we will first need a detailed understanding of the properties of both cell types. We will use five main techniques 1) Fast confocal imaging to measure intracellular calcium levels in pacemaking and smooth muscle cells and individual muscle bundles ; 2) the perforated patch-clamp technique to determine the ionic basis of the electrical activity; 3) RT-PCR, including real-time quantitative PCR to measure differences in channel expression in both cell types 4) Intracellular microelectrode recording to determine the source of pacemaking electrical activity in the whole tissue and 5) Isometric tension recordings to establish the contribution of IC and SMC to the generation of myogenic tone. We know from previous indirect evidence and from our preliminary data that the rhythmic electrical activity results from oscillatory calcium release within the IC. We will use fast confocal imaging of fluo-4 loaded IC to identify the initiating calcium event and the means by which it is amplified to a level sufficient to activate the ionic conductances underlying electrical activity. We know that frequency of oscillation is greatly influenced by external calcium levels so the next key task will be to determine the calcium influx pathway responsible. This will require an examination of the expression levels of channels known to mediate calcium entry using both RT-PCR and pharmacological approaches. Simultaneous imaging and patch clamp techniques will then be used to relate the intracellular calcium changes to membrane electrical events to determine how membrane potential changes affect intracellular calcium levels and vice-versa. Similar approaches will be used to elucidate the electrical and calcium-handling properties of SMC. When the fundamental properties of both IC and SMC have been elucidated we will turn our attention to the ways in which these are modified by excitatory and inhibitory neurotransmitters and then examine the contribution of IC to myogenic tone in isolated strips of urethra
Keywords: Address; Affect; Alimentary Canal; alimentary tract; Attention; Autonomic Nerve; autonomic nerve; Autonomic nerve structure; base; biological signal transduction; Bioniche Brand of Carbachol; Blood Coagulation Factor IV; Body Tissues; Ca++ element; Calcium; Carbachol; Carbacholine; Carbocholine; Cell Communication and Signaling; Cell Signaling; cell type; Cells; Coagulation Factor IV; Data; digestive canal; Digestive Tract; Electrodes, Miniaturized; Electrophysiology; Electrophysiology (science); Endogenous Nitrate Vasodilator; endothelial cell derived relaxing factor; Endothelium-Derived Relaxing Factor; Ethanaminium, 2-((aminocarbonyl)oxy)-N, N, N-trimethyl-, chloride; Event; Exhibits; Factor IV; Family; Feedback; Fluo 4; Frequencies (time pattern); Frequency; Gastrointestinal Tract; Gastrointestinal tract structure; Generations; GI Tract; ICC (Interstitial cell of Cajal); Image; imaging; Individual; interstitial cell; Interstitial Cell of Cajal; Interstitial cell of Cajal (ICC); Intracellular Communication and Signaling; Investigators; Isometric Exercise; Isometrics; Leiomyocyte; Mammals, Rabbits; Measures; Mechanics; Mediating; member; Membrane; Membrane Potentials; membrane structure; Methods and Techniques; Methods, Other; Microelectrodes; Modeling; Mononitrogen Monoxide; Muscle; Muscle Tissue; Muscle, Involuntary; Muscle, Smooth; Muscle-Setting Exercise; Myocytes, Smooth Muscle; Nerve Transmitter Substances; Neurophysiology / Electrophysiology; Neurotransmitters; Nitric Oxide; Nitric Oxide, Endothelium-Derived; Nitrogen Monoxide; Nitrogen oxide; Nitrogen Protoxide; NutraMax Brand of Carbachol; Oryctolagus cuniculus; Pace Stimulators; Pacemakers; Patch-Clamp Technics; Patch-Clamp Techniques; pathway; Pathway interactions; Pharmacology; Property; Property, LOINC Axis 2; Rabbit, Domestic; Rabbits; recruit; Recruitment Activity; Research Personnel; Researchers; response; Resting Potentials; reverse transcriptase PCR; Reverse Transcriptase Polymerase Chain Reaction; Role; RT-PCR; RTPCR; Signal Transduction; Signal Transduction Systems; Signaling; Smooth muscle (tissue); Smooth Muscle Cells; Smooth Muscle Myocytes; Smooth Muscle Tissue Cell; social role; Source; Static Exercise; Stimulators, Electrical, Pace; Techniques; Testing; Time; Tissues; Transmembrane Potentials; Urethra; urethral
Project start date: 2005-08-01
Project end date: 2011-05-31
Budget start date: 1-JUN-2009
Budget end date: 31-MAY-2011
PFA/PA: PA-03-136
5R01DK068565-05 (2009): $172207
TARGETED EXPRESSION OF ATOH1 IN COCHLEAR SUPPORTING CELLS
A Mark
Emerson Collegecity: Boston country: United States (us)
Grant 5R03DC010065-03 from National Institute On Deafness And Other Communication Disorders
Abstract: This research involves the biological approach to the treatment of hearing loss. It is designed to investigate the mechanisms involved in mammalian hair cell regeneration. The proposed experiments build upon the observation that global expression of the Atoh1 gene in cochlear cells is sufficient for hair cell genesis. This proposal will test the hypothesis that specific populations of cochlear supporting cells are able to differentiate into hair cells. To accomplish this, Atoh1 will be expressed 1) in a dose-dependent manner, and 2) specifically in the cochlear supporting cells that reside directly beneath the hair cells. The basic experimental protocol will be as follows. Cultured murine organs of Corti will be electroporated with an inducible form of Atoh1. Atoh1 expression will be limited to the supporting cells directly beneath the hair cells because it will be placed under the regulatory control of the GFAP promoter (selectively expressed in the inner phalangeal, inner border, pillar and Dieters´ cells) and GLAST promoter (inner border and inner phalangeal cell). Next, hair cells will be killed and then Atoh1 will be upregulated in these specific supporting cells. The ability for these specific supporting cell types to develop into hair cells will be observed using time lapse video microscopy, electron microscopy, and immunohistochemical expression of hair cell specific markers such as myosin 7a. Relevance The long-term goal of this research is to treat hearing loss with more effective therapies than provided by hearing aids or cochlear implants. Specifically, this research is designed to investigate the basic mechanisms by which the auditory sensory cells, or hair cells, can regenerate in mammals. The overall hypothesis is that replacement of lost hair cells will result in a superior therapy for the treatment of hearing loss
Keywords: Animal Model; Arts; Auditory; base; Biological; Biological Assay; Cell physiology; cell type; Cells; Cessation of life; Characteristics; Cilia; Cochlear Implants; design; Development; Diet; Dose; Down-Regulation; effective therapy; Effectiveness; Electron Microscopy; Engineering; Enhancers; Environment; Exhibits; Foundations; Future; gene delivery system; Generations; Genes; Gentamicins; GLAST Protein; Glial Fibrillary Acidic Protein; Goals; hair cell regeneration; Hair Cells; Hearing Aids; hearing impairment; Histologic; Hormones; Inner Supporting Cell; Killings; Label; Labyrinth; Labyrinth Supporting Cells; Lead; Mammals; Measures; Mediating; Modeling; mouse model; Mus; Myosin ATPase; Natural regeneration; Organ of Corti structure; Outer Hair Cells; Pillar Cell; Population; Production; Promotor (Genetics); Protocols documentation; Research; research study; selective expression; Sensory; Stem cells; Supporting Cell; System; Tamoxifen; Testing; Thiamine; time use; Transgenic Organisms; Up-Regulation (Physiology); Video Microscopy
Relevance: SF424(R&R) Other Project Information, Item 7: The long-term goal of this research is to treat hearing loss with more effective therapies than provided by hearing aids or cochlear implants. Specifically, this research is designed to investigate the basic mechanisms by which the auditory sensory cells, or hair cells, can regenerate in mammals. The overall hypothesis is that replacement of lost hair cells will result in a superior therapy for the treatment of hearing loss
Project start date: 2009-06-01
Project end date: 2012-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PAR-07-287
5R03DC010065-03 (2011): $144562
7R03DC010065-04 (2011): $171000
ALTERED LIPID DROPLET TRAFFICKING: ROLE IN ALCOHOLIC FATTY LIVER DISEASE
A Mark
University Of Nebraska Medical Centercity: Omaha country: United States (us)
Grant 1R01AA020735-01 from National Institute On Alcohol Abuse And Alcoholism
Abstract: This proposal is in response to the Request for Applications (RFA) from NIAAA entitled "Alcohol-Induced Metabolic and Hepatic Injury (AIMHI)". The goal of this multiple-PI application is to examine how ethanol exposure can lead to impaired membrane trafficking events in the liver hepatocyte that results in increased fat accumulation due to altered dynamics of large fat storage organelles termed lipid droplets (LDs). During alcoholic fatty liver disease (AFLD), almost all heavy drinkers develop fatty liver, which is marked by the aberrant and significant accumulation of intrahepatocellular fatty acids in the form of LDs. The cellular processes contributing to this marked increase in the number and size of these organelles is considered a prime target for therapeutic intervention to block further progression as it is an initial stage of the injury, and thus reversible. It appears that the cyclical formation, accumulation and subsequent metabolism of LDs are dependent on an intricate trafficking process in the hepatocyte that share marked similarities with the endocytic and secretory trafficking pathways. We have found that central to LD dynamics in hepatocytes are several GTPases (dynamins and rabs in particular) that can act as molecular switches to regulate membrane traffic. In preliminary data obtained by Drs. Casey and McNiven in a recently funded "Challenge Grant" it was shown that disruption of these GTPases (by ethanol or by experimental manipulation) could dramatically increase accumulation of LDs in the liver cell. These findings support our central hypothesis that ethanol exposure leads to an impairment of the membrane trafficking machinery in the hepatocyte that attenuates LD disassembly resulting in hepatic steatosis. The two principal investigators involved in this proposed project have complementary strengths; one is an expert in alcoholic-induced liver damage (Casey), and the other in hepatocyte membrane-cytoskeleton dynamics (McNiven). We will utilize a variety of state-of-the art membrane trafficking and imaging technologies that are novel to this area of research in our investigations of how LD formation and utilization is affected by ethanol in hepatocytes. Novel and innovative biological concepts pursued in this proposal include one, ETOH disrupts vesiculation of LDs normally used to aid in lipolysis, two, the hepatocyte endocytic machinery is utilized in this LD vesiculation process and compromised by ETOH exposure, three, ubiquitinylation of LD proteins is markedly attenuated by ETOH and aids in targeting of the LDs to the lysosome for subsequent degradation. Successful completion of these studies will provide new technologies and insights as to how ethanol affects LD dynamics in the liver, and provide information which could lead to therapeutic strategies aimed at reducing the severity of steatosis and blocking the further progression to steatohepatitis, fibrosis and cirrhosis. The goal of this proposal is to examine how alcohol exposure can lead to impaired membrane trafficking events in the liver which would eventually result in increased fat due to altered dynamics of the large fat storage organelles, lipid droplets (LDs). We hypothesize that ethanol exposure leads to hepatic steatosis as a result of attenuated LD vesiculation and subsequent trafficking to lysosomes. This leads to altered LD disassembly which then contributes to hepatic steatosis. Successful completion of these studies will provide novel insights as to how ethanol affects LD dynamics in the liver cells, and provide information which could lead to therapeutic strategies that might reduce the severity of steatosis and block the further progression to steatohepatitis, fibrosis and cirrhosis
Keywords: Actins; Acute; Address; Affect; Alcohol abuse; alcohol exposure; Alcoholic beverage heavy drinker; Alcoholic Fatty Liver; Alcoholic Liver Diseases; Alcohols; Area; Attenuated; base; Biological; Capsid Proteins; Caveolae; Caveolins; Cell physiology; Cellular biology; Cellular Membrane; Chronic; Cirrhosis; Cytoskeleton; Data; Dynamin; Dynamin 2; Enzymes; Ethanol; Event; Family; Family member; Fatty acid glycerol esters; Fatty Acids; Fatty Liver; Fibrosis; Funding; Goals; Grant; Guanosine Triphosphate Phosphohydrolases; Health; Hepatic; Hepatocyte; Imaging technology; Impairment; in vivo; Injury; innovation; insight; Investigation; Knockout Mice; Laboratories; Lead; lipid metabolism; Lipids; Lipolysis; Liver; Liver diseases; Lysosomes; Mediating; Membrane; Membrane Protein Traffic; Metabolic; Metabolism; Molecular; National Institute on Alcohol Abuse and Alcoholism; new technology; novel; Organelles; Pathway interactions; prevent; Principal Investigator; problem drinker; Process; Proteins; Recruitment Activity; Request for Applications; Research; response; Role; scaffold; Severities; Signal Transduction; src-Family Kinases; Staging; Steatohepatitis; Surface; System; Testing; Therapeutic; Therapeutic Intervention; trafficking
Relevance: The goal of this proposal is to examine how alcohol exposure can lead to impaired membrane trafficking events in the liver which would eventually result in increased fat due to altered dynamics of the large fat storage organelles, lipid droplets (LDs). We hypothesize that ethanol exposure leads to hepatic steatosis as a result of attenuated LD vesiculation and subsequent trafficking to lysosomes. This leads to altered LD disassembly which then contributes to hepatic steatosis. Successful completion of these studies will provide novel insights as to how ethanol affects LD dynamics in the liver cells, and provide information which could lead to therapeutic strategies that might reduce the severity of steatosis and block the further progression to steatohepatitis, fibrosis and cirrhosis
Project start date: 2011-08-10
Project end date: 2016-07-31
Budget start date: 10-AUG-2011
Budget end date: 31-JUL-2012
1R01AA020735-01 (2011): $453328
GENETIC CONTROL OF PANCREATIC ENDOCRINE CELL DEVELOPMENT
A Mark, Professor
Vanderbilt Universitycity: Nashville country: United States (us)
Grant 5U01DK089523-02 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: This project will use a team-based approach to pursue three directly interrelated areas of investigation important for learning to make new pancreatic beta cells from other cell types. In Aim 1 we seek to gain a deeper understanding of the molecular events that dictate formation of multiple endocrine cell types during pancreas development. This will be achieved by isolating a series of highly purified progenitor cell populations, performing digital gene expression analysis, and developing bioinformatics strategies for characterizing the differences among discrete cellular populations that will be temporally or genetically informative. In Aim 2 we will seek to utilize the knowledge gained in Aim 1 to determine the veracity of protocols being used to direct the differentiation of hESCs towards pancreatic cell fates and to rationally improve these protocols by monitoring the expression of gene clusters that are specifically activated or repressed during mouse development. In Aim 3 we will develop new mouse lines in which the expression of three transcription factors that have been reported to be capable of transdifferentiating pancreatic acinar to beta cells can be easily modulated by the administration of doxycycline. These mice will be used to explore how transdifferentiation actually occurs and to determine the extent to which the newly generated beta cells are functional and exhibit a gene expression profile similar to authentic beta cells. This project is based on the premise/hypothesis that multiple gene regulatory networks, which are normally set up during mouse development, must be established during directed or trans-differentiation of other cell types to achieve the beta cell-like functionalities necessary for clinical use. Greater knowledge of pancreas-specific gene regulatory networks, how they are established and differ among related cell populations, and determining whether they are present or absent in experimentally-derived cellular populations, will serve as a platform both for new discovery and protocol improvements. The six investigators in this project have a track record of productive collaborative interactions and bring specific knowledge and abilities necessary to accomplish these goals. Thus, it is anticipated that this project will generate important resources that will not only advance two of the overarching goals of the Beta Cell Biology Consortium but also have broad scientific impact and utility. Type 1 and Type 2 diabetes are diseases that cause significant morbidity and mortality and thus have an adverse economic impact. Both diseases are characterized by the destruction or dysfunction of insulin-secreting pancreatic beta cells. This application seeks to gain key information for developing new, cell-based replacement therapies that hold promise for achieving better glucose control than is currently possible
Keywords: Acinar Cell; Area; base; Beta Cell; Bioinformatics; Biological Assay; blood glucose regulation; cell type; Cells; Cellular biology; Clinical; Data; Data Set; Development; digital; Disease; DNA Sequence; Doxycycline; economic impact; Embryo; Endocrine; Epitopes; Event; Exhibits; Functional disorder; Gene Cluster; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Generations; Genetic; Goals; Human; human embryonic stem cell; human embryonic stem cell line; improved; In Vitro; in vivo; insight; Insulin; Investigation; Kinetics; Knowledge; Lead; Learning; Methods; Molecular; Molecular Profiling; Monitor; Morbidity - disease rate; Mortality Vital Statistics; mouse development; mouse model; Mus; Mutant Strains Mice; network models; novel; overexpression; Pancreas; pancreas development; Phenotype; Population; Principal Investigator; Proteins; Protocols documentation; public health relevance; Reagent; Regulator Genes; Replacement Therapy; Reporting; Research Personnel; Resources; RNA; Role; Series; Signal Transduction; Signaling Pathway Gene; Staging; stem cell differentiation; stem cell population; Stem cells; Stream; Structure of beta Cell of islet; Testing; tool; transcription factor; transdifferentiation; Translating; type I and type II diabetes; web site
Project start date: 2010-09-20
Project end date: 2015-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: RFA-DK-09-011
5U01DK089523-02 (2011): $1298704
WHOLE-BODY PET/CT ASSESSMENT OF TUMOR PERFUSION USING GENERATOR-PRODUCED 62CU
A Mark, Professor
Indiana Univ-purdue Univ At Indianapoliscity: Indianapolis country: United States (us)
Grant 4R01CA140299-03 from National Cancer Institute
Abstract: This project will evaluate a non-invasive PET method for assessment of tumor perfusion using generator- produced copper-62. The proposed method will be suitable for implementation at any clinical PET center in the U.S., complementing current clinical whole-body PET 18F-FDG studies to assess tumor metabolism. The project´s clinical focus is patients with head-and-neck cancer, where literature evidence indicates that tumor perfusion measurements can be predictive of response to therapy. Patients with localized or locally advanced head and neck cancer, who are to receive concurrent chemo-radiation therapy, will receive the investigational 62Cu-ETS radiopharmaceutical for "whole-body" PET/CT imaging to assess tumor perfusion. The 62Cu-ETS imaging will occur immediately prior to scheduled standard baseline and post-therapy clinical PET/CT with 18F-FDG. A subset of patients will also be imaged using 15O-water to provide an independent reference measure of tumor perfusion. The 62Cu-ETS tumor perfusion results will be quantified using an image-derived arterial input function. Global and regional measures of tumor perfusion will be compared to the findings from 18F- FDG imaging, as well as to changes in tumor size using RECIST criteria. Subjects will be seen for follow-up one month after completion of treatment; then a minimum of every three months. The imaging results will be examined for correlations with independent measures of clinical outcome, including twenty-four month actuarial local progression-free survival, regional progression-free survival, distant metastases-free survival and overall survival. Therapy failure will be defined as biopsy-proven recurrent disease, or imaging results inconsistent with any other explanation than disease recurrence or metastases. Planned neck dissection following chemo-radiotherapy showing the presence of residual viable tumor cells will not be classified as regional failure, as this will be considered completion of the planned curative therapy. The project both requires, and exploits, radiopharmaceutical production technologies under development by Proportional Technologies, Inc., and the expertise of academic collaborators from the Purdue University School of Pharmacy and the Indiana University School of Medicine. Head and neck cancers account for about 3% of adult malignancies in the United States, and disproportionately affect African Americans. This project initiates clinical evaluation of a PET imaging method to evaluate tumor blood flow, using imaging technology that can be readily implemented at medical centers throughout the country. This PET method is expected to improve the physician´s ability to make optimal treatment decisions for head and neck cancer patients
Keywords: Accounting; Adult; Affect; African American; base; Beds; Biopsy; Blood; Blood flow; Chemistry; Clinical; clinical application; clinical efficacy; clinically relevant; Complement; Copper; Country; Cyclotrons; Data; Development; Disease; Disease Progression; Distant Metastasis; Evaluation; experience; Failure (biologic function); follow-up; Foundations; Gold; Half-Life; Head and Neck Cancer; head and neck cancer patient; Health; Image; imaging modality; Imaging technology; improved; in vivo; Indiana; Investigation; Left atrial structure; Left ventricular structure; Life; Link; Literature; Malignant Neoplasms; Measurement; Measures; Medical center; Medical Oncology; medical schools; Metabolic; Metabolism; Methods; Multi-Institutional Clinical Trial; Neck Dissection; Neoplasm Metastasis; neoplastic cell; NIH Program Announcements; North America; novel strategies; Outcome; Patients; Pattern; Perfusion; Pharmacy Schools; Physicians; Physiology; Positioning Attribute; Positron-Emission Tomography; Production; professor; Progression-Free Survivals; Protocols documentation; Quantitative Evaluations; Radiation Oncology; Radiation therapy; Radioisotopes; Radionuclide Generators; Radiopharmaceuticals; Recurrence; Recurrent disease; Regional Perfusion; research clinical testing; Residual state; response; Schedule; Site; System; Technology; Testing; Tracer; tumor; Tumor Markers; United States; Universities; uptake; Validation; Water; whole body imaging
Relevance: Head and neck cancers account for about 3% of adult malignancies in the United States, and disproportionately affect African Americans. This project initiates clinical evaluation of a PET imaging method to evaluate tumor blood flow, using imaging technology that can be readily implemented at medical centers throughout the country. This PET method is expected to improve the physician´s ability to make optimal treatment decisions for head and neck cancer patients
Project start date: 2009-08-01
Project end date: 2013-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PAR-07-214
4R01CA140299-03 (2011): $420747
NEUROIMAGING OF AGE-RELATED CHANGES IN SPEECH RECOGNITION
A Mark, Assistant Professor
Medical University Of South Carolinacity: Charleston country: United States (us)
Abstract: This project examines the structure and function of neural systems that are hypothesized to contribute to age-related declines in speech recognition. Large age-related differences in speech recognition are observed in complex and demanding listening environments for reasons that are unclear. Aging brains undergo extraordinary changes and there is little understanding of how these changes limit or preserve cognitive abilities. We propose to track the aging of two neural systems that play central roles in hypotheses for declines in speech recognition. Aim 2.1 tests the hypothesis that age-related anatomical declines in brain regions that support speech recognition lead to increased reliance on attention-related frontal cortex for word recognition in normal hearing adults. Aim 2.2 tests the hypothesis that older adults with normal hearing exhibit speech recognition declines when additive anatomical declines within speech-related and attention-related systems limit the ability to attend to degraded speech. Aim 2.3 tests the hypothesis that the most common form of age-related hearing loss, metabolic presbyacusis, leads to compensatory changes within speech-related and attention-related systems. This project uses brain activation experiments to define speech-responsive brain regions where anatomical declines may explain the connection between the aging brain and speech recognition difficulties. This project will provide an understanding of the age-related neurobiological changes that people with normal hearing and with hearing loss experience and thereby provide a foundation for improving the speech recognition of older adults through the development of intervention strategies that are based on the peripheral and central nervous system changes that occur with age
Keywords: Abbreviations; Accounting; Address; Adult; Affect; Age; age related; Aging; aging brain; Anisotropy; Anterior; Attention; base; Behavioral; Brain; Brain region; Brodmann`s area; Characteristics; cingulate cortex; Clinical; Clinical Research; clinically relevant; Cognitive; Complex; Data; design; Development; Diffusion Magnetic Resonance Imaging; Elderly; entorhinal cortex; Environment; Exhibits; experience; Foundations; frontal lobe; frontal lobe cortex; Functional Magnetic Resonance Imaging; Funding; Galvanic Skin Response; Goals; Hearing; hearing impairment; Hippocampus (Brain); improved; Individual; Inferior frontal gyrus; interest; Intervention; Lead; Link; Magnetic Resonance Imaging; Measures; Metabolic; Middle frontal gyrus structure; morphometry; Neuraxis; Neurobiology; neuroimaging; Neurophysiology - biologic function; Pathway interactions; Performance; Peripheral; Phenotype; Play; Presbycusis; programs; Psyche structure; relating to nervous system; Reliance; Research; research study; Role; Speech; speech recognition; Stimulus; Structure; Structure of superior temporal sulcus; Superior temporal gyrus; System; Temporal Lobe; Testing; therapy design; Thick; white matter
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
5P50DC000422-24_0009 (2011): $396151
Sponsored Links Excellgen http://Excellgen.com
A SYSTEMS BIOLOGY APPROACH TO THE DEVELOPMENT OF CANCER BIOMARKERS
A Mark
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 5U01CA111275-07 from National Cancer Institute
Abstract: This grant represents the first renewal of the UM EDRN Biomarker Development Lab (BDL) which was initiated 5 years ago. During this brief time period, our group has characterized a number of important prostate cancer biomarkers, the most noteworthy being the TMPRSS2-ETS gene fusions found in a majority of prostate cancers. This discovery led to first inaugural AACR Team Science Award in 2007. Looking forward, we propose extending our work in the discovery and refinement of biomarkers to facilitate the accurate diagnosis of prostate cancer using the TMPRSS2-ETS rearrangements as a foundation. We will also take on the significant mission of developing biomarkers to predict aggressive prostate cancer with the goal of distinguishing indolent from aggressive prostate cancer either prior to diagnosis or at the time of biopsy diagnosis. This study takes a systems biology approach to develop clinically relevant prostate cancer biomarkers for detection and risk assessment. In Aim 1, we will extend work from the prior funding period to develop prostate cancer specific biomarkers to accurately diagnose prostate cancer and thus decrease unnecessary biopsies. Aims 2 and 3 focus on the important clinical need to develop biomarkers to distinguish significant from insignificant disease. Aim 2 will use high grade cancer as a surrogate of aggressive disease and Aim 3 we will use two clinically developed risk assessment tools as a surrogate measure of aggressive disease. A biomarker for aggressive disease would impact screening detection and clinical management of prostate cancer. The primary platform technologies we will employ (and have credible expertise) include next generation transcriptome sequencing, Affymetrix SNP arrays, lllumina DASL, Luminex xMAP-based multiplex antigen panels and mass spectrometry based metabolomics. The development of prostate cancer biomarkers for accurate diagnosis and risk assessment are urgently needed as recognized by the EDRN. Our proposal is highly ambitious given the wide range of discovery platforms proposed. Our team approach also extends beyond our BDL and into the EDRN Clinical Validation Center (CVC) where both PIs of this application have played roles in the Michigan/Harvard/WCMC CVC collection of over 1800 samples on EDRN protocol. Finally, our group has actively participated in the EDRN biomarker community and anticipates continuing to work with other BDL and CVCs to facilitate the overall mission of the EDRN
Keywords: Age; American Association of Cancer Research; Antigens; Award; base; biomarker; Biopsy; Clinical; Clinical Management; Clinical Treatment; clinically relevant; clinically significant; cohort; Collection; Communities; Detection; Development; Diagnosis; Disease; DNA Sequence Rearrangement; Early Detection Research Network; Foundations; Funding; Future; Gene Expression Profile; Gene Fusion; Goals; Grant; Healthcare Systems; Indolent; Malignant neoplasm of prostate; Malignant Neoplasms; Mass Spectrum Analysis; Measures; men; metabolomics; Michigan; Mission; next generation; novel; Plasma; Play; Population; Predictive Value; Prostate; Protocols documentation; Recording of previous events; Risk Assessment; Role; Sampling; Science; Screening for Prostate Cancer; Screening procedure; Specificity; Systems Biology; Technology; Time; TMPRSS2 gene; tool; urinary; Urine; Validation; validation studies; Work
Relevance: Recent studies suggest that regardless of clinical treatment offered, most men with clinically localized prostate cancer at time of initial diagnosis do not die of their disease but from other causes. As the U.S. population ages, the number of prostate cancer cases will increase representing an important impact on our health care system. Taken together, we urgently need the next generation prostate cancer screening biomarkers that will have high specificity and be associated with clinically significant disease
Project start date: 2004-09-20
Project end date: 2015-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5U01CA111275-07 (2011): $695128
2U01CA111275-06 (2010): $703683
MONOAMINE AND HALLUCINOGEN EFFECTS ON RODENT BEHAVIOR
A Mark, Professor
University Of California San Diegocity: La Jolla country: United States (us)
Grant 2R01DA002925-27A1 from National Institute On Drug Abuse
Abstract: This competitive renewal application seeks continued support for a long-standing and very productive project that uses rodent models to elucidate mechanisms underlying the behavioral effects of synthetic hallucinogenic drugs of abuse, including LSD and substituted amphetamines, and hallucinogenic natural products used in recreational, ritual, or religious contexts, including psilocybin mushrooms (psilocin), peyote cactus (mescaline), and Ayahuasca tea (DMT, 5MeODMT). Based on the profound effects of hallucinogens on responses to sensory and emotional stimuli in humans, hallucinogenic drug effects in rats and mice are assessed using two complementary behavioral paradigms that have direct counterparts in the study of human behavior. These translational paradigms are prepulse inhibition of the startle response, an operational measure of sensorimotor gating that is deficient in some psychiatric disorders, and rat and mouse Behavioral Pattern Monitors that provide a multivariate profile of exploratory and locomotor responses matching that used to assess psychiatric patients and psychostimulant abusers in the human Behavioral Pattern Monitor. These computerized systems assess activity, exploration, and behavioral organization - three major aspects of mammalian behavior in a novel environment. In addition, the hallucinogen-induced head-twitch response in rodents is used for specific questions. Selected drug studies are complemented by studies of mutant mice having specific deficits in serotonin or glutamate receptor subtypes. This combination of pharmacological and genetic manipulations provides converging approaches to hypothesis testing. The project has 3 specific aims. Aim 1 is to characterize and identify the mechanism by which synthetic equivalents of Ayahuasca tea ("Pharmahuasca") alter exploratory behavior in rats. Aim 2 tests specific hypotheses regarding the different serotonin receptor subtypes that mediate the behavioral effects of phenylalkylamine and indoleamine hallucinogens in mice. Given the important species differences in the effects of many serotonergic and dopaminergic drugs, these results will be compared with previous data from rats to better understand the relevance of the animal models to drug effects in humans. In light of the recent resumption of human studies with hallucinogens, and reports indicating that hallucinogens may possess clinical efficacy, a more complete understanding of the action of these drugs is urgently needed. Aim 3 is to test the hypothesis that metabotropic glutamatergic mGlu2/3 and mGlu5 receptors modulate the behavioral effects of serotonergic hallucinogens, extending recent findings suggesting that common pathways contribute to the effects of serotonergic and glutamatergic hallucinogens. These studies are responsive to PA-07-374 "Psychopharmacology of Widely Available Psychoactive Natural Products". This research uses behavioral measures that can be translated directly into parallel measures of human behavior to elucidate the neurobiological mechanisms responsible for the acute effects of hallucinogens, which presumably lead to the recreational use of these drugs of abuse. Despite hundreds of years of human experimentation and recent increases in the use of hallucinogens either as religious sacraments or as "Club Drugs" in recreational contexts, very little is known about the brain mechanisms underlying the behavioral effects of hallucinogens. This long-standing project uses rodent models to identify the neurobiological mechanisms of action responsible for the effects of naturally occurring hallucinogens, such as psilocybin, mescaline, and Ayahuasca, and synthetic hallucinogens such as LSD. Such information is critical to understand the consequences of the use of these compounds and to provide models of psychosis that could help identify novel therapeutic targets for neuropsychiatric disorders
Keywords: Abbreviations; Acute; Address; Aftercare; Agaricales; Agonist; Alkaloids; Amphetamines; Animal Model; Banisteriopsis; base; Behavior; behavior measurement; Behavioral; Behavioral Paradigm; Binding (Molecular Function); Biological Factors; Brain; Cactaceae; Carbolines; Central America; Characteristics; Chronic; clinical efficacy; club drug; Complement; Complex; computerized; Data; Disease; Dopaminergic Agents; Drug effect disorder; drug of abuse; ecstasy; emotional stimulus; Environment; Exploratory Behavior; frontal lobe; Functional disorder; Funding; Genetic; genetic manipulation; Glutamate Receptor; Glutamates; Goals; GRM5 gene; Hallucinogens; Harmaline; Head; HTR2A gene; Human; Human Experimentation; indoleamine; Ketamine; Lead; Light; Measures; Mediating; Mediation; Mental disorders; Mescaline; Metabolism; metabotropic glutamate receptor 2; Modeling; Monitor; monoamine; Monoamine Oxidase Inhibitors; Mus; Mutant Strains Mice; neurobiological mechanism; neurochemistry; neuropsychiatry; new therapeutic target; novel; Pathway interactions; Patients; Pattern; Peyote preparation; Pharmaceutical Preparations; phenylalkylamine; prepulse inhibition; Psychiatric therapeutic procedure; Psychopharmacology; psychostimulant; Psychotic Disorders; public health relevance; Rattus; receptor; Receptor Activation; Regulation; Religion and Spirituality; Reporting; Research; research study; Resistance; response; Ritual compulsion; Rodent; Rodent Model; Route; sensory stimulus; Serotonin; Serotonin Agents; serotonin receptor; snuff; species difference; System; Tea; Testing; Time; Translating; Work
Relevance: Narrative Despite hundreds of years of human experimentation and recent increases in the use of hallucinogens either as religious sacraments or as "Club Drugs" in recreational contexts, very little is known about the brain mechanisms underlying the behavioral effects of hallucinogens. This long-standing project uses rodent models to identify the neurobiological mechanisms of action responsible for the effects of naturally occurring hallucinogens, such as psilocybin, mescaline, and Ayahuasca, and synthetic hallucinogens such as LSD. Such information is critical to understand the consequences of the use of these compounds and to provide models of psychosis that could help identify novel therapeutic targets for neuropsychiatric disorders
Project start date: 1981-09-30
Project end date: 2016-01-31
Budget start date: 1-APR-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-07-374
2R01DA002925-27A1 (2011): $309000
1/3-IMPROVING METABOLIC PARAMETERS OF ANTIPSYCHOTIC CHILD TREATMENT (IMPACT)
A Mark, Professor
Johns Hopkins Universitycity: Baltimore country: United States (us)
Grant 5R01MH080270-04 from National Institute Of Mental Health
Abstract: This collaborative R01 application, entitled "Improving Metabolic Parameters of Antipsychotic Child Treatment" (IMPACT), is re-submitted in response to NIMH PA-07-092 (Collaborative R01s for Clinical and Services Studies of Mental Disorders, AIDS and Alcohol Use Disorders) and PA-07-078 (Treatment-Emergent Adverse Effects of Psychotropic Medication). This five-year, three-site study will be conducted at Johns Hopkins University/University of Maryland (M. Riddle PI), University of North Carolina (L. Sikich PI) and Zucker Hillside Hospital (C. Correll PI). The overarching goal is to identify improved treatments for children and adolescents who have gained substantial weight on 2nd generation antipsychotic medications (SGAs). An "improved treatment" would 1) provide adequate psychiatric symptom relief, 2) reduce SGA-induced weight gain, and 3) reduce SGA-induced insulin resistance and hyperlipidemia. Reductions in obesity, insulin resistance and hyperlipidemia are of great public health importance because they are factors strongly associated with type 2 diabetes and premature cardiovascular disease. The specific objective of the proposed study is to obtain data about the relative risks and benefits of 2 medication strategies for reducing SGA-associated weight gain and metabolic problems in youth, in comparison to control treatment. This study, which builds on extensive pilot data, will use a hybrid efficacy/effectiveness design to evaluate two competing medication approaches for the management of weight gain and metabolic side effects in youngsters on SGAs. The study is designed so that findings can be generalized to other clinical settings. We plan to enroll 240 participants, ages 8-17 years, who 1) are currently treated with one of the three most commonly prescribed antipsychotics (risperidone, quetiapine or olanzapine), 2) have current BMI >85th percentile and have experienced substantial weight gain (>10%) during the past year while treated with their current SGA, 3) meet DSM-IV diagnostic criteria for a schizophrenia spectrum disorder or bipolar spectrum disorder, and 4) are psychiatrically stable. All participants will be randomized to one of three conditions 1) continue current SGA (control group), 2) metformin + current SGA, or 3) staggered switch to aripiprazole with discontinuation of current SGA. The study will include a 3-week screening/baseline period and 24 weeks of treatment. The primary outcome variable is change in weight as reflected by change in BMI z-score. Secondary outcomes include change in BMI percentile, change in weight as percent baseline weight, body fat mass, insulin sensitivity, lipids, prevalence of metabolic syndrome, and all cause treatment discontinuation. Individuals who experience continued excessive weight gain or psychiatric destabilization will be removed from the trial and treated as clinically indicated by the research team. The results of this project will inform future treatment for children and adolescents with major psychiatric disorders. The results are also likely to lead to treatments that improve their health and longevity
Keywords: Acquired Immunodeficiency Syndrome; Adolescent; Adult; Adverse effects; Age; alcohol use disorder; Antipsychotic Agents; aripiprazole; arm; Benefits and Risks; Body fat; Body mass index; Cardiovascular Diseases; Child; Clinical; Clinical Services; Communities; Control Groups; Data; design; diabetic; Diagnostic; Disease; DSM-IV; Dual-Energy X-Ray Absorptiometry; Effectiveness; electric impedance; Enrollment; experience; Future; Generations; Glucose; Goals; Health; Hospitals; Hybrids; Hyperlipidemia; improved; indexing; Individual; Insulin; Insulin Resistance; insulin sensitivity; LDL Cholesterol Lipoproteins; Lead; Lipids; Longevity; Maryland; Measurement; Measures; meetings; Mental disorders; Metabolic; Metabolic syndrome; Metformin; National Institute of Mental Health (U.S.); Non-Insulin-Dependent Diabetes Mellitus; North Carolina; Obesity; OGTT; olanzapine; Outcome; Participant; Pharmaceutical Preparations; Placebos; Population Study; premature; Prevalence; primary outcome; public health medicine (field); Quality of life; quetiapine; Randomized; Relative Risks; Research; response; Risperidone; Schizophrenia; Screening procedure; secondary outcome; Secondary to; Site; Symptoms; Time; Translations; Triglycerides; United States; Universities; Weight; Weight Gain; Youth
Project start date: 2008-09-22
Project end date: 2013-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-07-092
5R01MH080270-04 (2011): $364428
REGULATION OF ALCOHOL-INDUCED FATTY LIVER DISEASE BY LIPID DROPLET TRAFFICKING
A Mark
University Of Nebraska Medical Centercity: Omaha country: United States (us)
Grant 5RC1AA019032-02 from National Institute On Alcohol Abuse And Alcoholism
Abstract: This application addresses broad Challenge Area (11) Regenerative Medicine and specific Challenge Topic 11-AA-102 Roles of Cellular Organelles and the Cytoskeleton in Alcohol-induced Organ Damage. Alcohol abuse and alcohol-induced liver disease are a major health concern in the US and worldwide. Alcoholic fatty liver disease (AFLD) is marked by the aberrant accumulation of intracellular fatty acids in hepatocytes and can progress to hepatitis, fibrosis, cirrhosis, and liver failure. Steatosis, the accumulation of fat in hepatocytes, is the reversible initial step of AFLD. As such, it is a prime target for therapeutic intervention to block AFLD progression. Intracellular lipids are stored in hepatocytes in lipid droplets, dynamic organelles that accumulate in excess in steatosis. However, the formation, regulation, and metabolism of lipid droplets are poorly understood. This proposal will focus on defining the mechanisms of lipid droplet trafficking, their interaction with other central intracellular organelles and how these processes are altered under conditions of ethanol exposure. Our central hypothesis is that chronic ethanol exposure alters the normal vesicle trafficking between lipid droplets and other membrane organelles in the hepatocyte, leading to fatty liver. The endoplasmic reticulum (ER), Golgi apparatus, and endosomal compartments have all been linked to lipid droplets. Two different laboratories expert in alcohol induced liver damage and hepatocellular membrane-cytoskeletal dynamics will work in synergy to determine the functions of each of these organelles in regulating lipid droplet formation and metabolism under normal conditions and following ethanol exposure to mediate the progression of AFLD. The goal of this proposal is to examine how impairments and alterations in trafficking and targeting of lipid droplets (LD) to specific organelles influences LD accumulation in steatosis and contributes to alcohol-induced fatty liver disease (AFLD). We hypothesize that chronic ethanol exposure alters the normal vesicle trafficking between lipid droplets and Golgi, endosomes, and endoplasmic reticulum, leading to fatty liver and subsequently hepatocellular damage. Successful completion of these studies will provide information which could lead to therapeutic strategies that might reduce the severity of steatosis and block the further progression to steatohepatitis, fibrosis and cirrhosis
Keywords: Actins; Acute; Address; Affect; Alcohol abuse; alcohol exposure; Alcoholic Fatty Liver; Alcoholic liver damage; Alcoholic Liver Diseases; Alcohols; Area; caveolin 1; Chronic; Cirrhosis; Cytoskeleton; Disease Progression; Endocytic Vesicle; Endoplasmic Reticulum; Endosomes; Equilibrium; Ethanol; Exposure to; Fatty acid glycerol esters; Fatty Acids; Fatty Liver; Fibrosis; Goals; Golgi Apparatus; Health; Hepatitis; Hepatocellular Damage; Hepatocyte; Impairment; information gathering; Laboratories; Lead; Link; lipid metabolism; Lipids; Liver diseases; Liver Failure; Mediating; Membrane; Metabolism; Microtubules; Monomeric GTP-Binding Proteins; novel; Organ; Organelles; Oxidative Stress; particle; Pathway interactions; Prevention; Process; protein transport; public health relevance; Regenerative Medicine; Regulation; Role; Severities; Staging; Steatohepatitis; Testing; Therapeutic; Therapeutic Intervention; trafficking; trans-Golgi Network; Transport Vesicles; Very low density lipoprotein; Vesicle; Work
Relevance: The goal of this proposal is to examine how impairments and alterations in trafficking and targeting of lipid droplets (LD) to specific organelles influences LD accumulation in steatosis and contributes to alcohol-induced fatty liver disease (AFLD). We hypothesize that chronic ethanol exposure alters the normal vesicle trafficking between lipid droplets and Golgi, endosomes, and endoplasmic reticulum, leading to fatty liver and subsequently hepatocellular damage. Successful completion of these studies will provide information which could lead to therapeutic strategies that might reduce the severity of steatosis and block the further progression to steatohepatitis, fibrosis and cirrhosis
Project start date: 2009-09-30
Project end date: 2012-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2012
5RC1AA019032-02 (2010): $498213
1RC1AA019032-01 (2009): $499999
DEVELOPMENT OF THERMOACOUSTIC TOMOGRAPHY BRAIN IMAGING
A Mark
Washington Universitycity: Saint Louis country: United States (us)
Grant 7R01EB010049-02 from National Institute Of Biomedical Imaging And Bioengineering
Abstract: Thermo acoustic tomography (TAT) is a rapidly emerging ultrasound-mediated hybrid imaging modality that promises to have a major impact on diagnostic imaging. TAT combines high ultrasonic resolution and strong microwave contrast in a single hybrid modality. Human brain imaging represents an important imaging application that can benefit tremendously by the development of TAT methods. Existing high-resolution human brain imaging modalities such as X-ray computed tomography (CT) and magnetic resonance imaging (MRI) are expensive and employ bulky and generally non-portable imaging equipment. Moreover, X-ray CT employs ionizing radiation and is unsafe for patients who need long time monitoring of brain diseases or injuries. Alternatively, ultrasonography is an established portable pediatric brain imaging modality, but its image quality degrades severely when employed after the closure of the fontanels and therefore is not effective for imaging adults. The development of TAT brain imaging methods would circumvent these limitations and result a powerful new brain imaging modality that would fill an important void left by the available techniques. The major technical challenge in TAT brain imaging is to compensate for the distortion introduced into the TAT measurement data by the skull. The broad objective of this proposal is to make TAT brain imaging a practical, useful, and highly effective brain imaging modality by developing robust image reconstruction methods that can account for skull-induced signal distortion and other physical factors. By use of information regarding the skull morphology and composition obtained from previously acquired adjunct image data, or alternatively from the TAT measurement data themselves, we will develop and investigate robust imaging models for TAT that account for the effects of skull-induced wave front aberrations and other physical factors related to the measurement process. We will develop reconstruction algorithms for obtaining accurate images from incomplete data sets that correspond to clinically useful measurement configurations. The developed methods will be systematically evaluated in computer-simulation and experimental studies. The first in vivo study of human TAT brain imaging will also be conducted. The specific aims of the project are (1) To develop imaging methodologies that incorporate the effects of skull-induced phase aberrations; (2) To develop image reconstruction algorithms for practical brain imaging scanning configurations; (3) To validate the reconstruction methods for TAT brain imaging in computer-simulation studies; and (4) To assess image quality in phantom and in-vivo studies. The development of thermo acoustic tomography brain imaging will yield a powerful and effective new modality for monitoring brain conditions such as strokes, tumors, and brain injuries. Its specific advantages over existing high-resolution human brain imaging modalities include 1) relatively low-cost, 2) portability that would permit near real-time imaging studies at bedside or in operating rooms, 3) use of non-ionizing radiation, and 4) measurement of structural and functional brain information that is complementary to that revealed by existing methods
Keywords: Accounting; Acoustics; Address; Adult; Algorithms; attenuation; base; Biophotonics; bone; Brain; Brain Diseases; Brain imaging; Brain Injuries; brain tissue; Childhood; Clinical; clinical application; Computer Simulation; cost; cranium; Data; Data Set; density; design; Development; Diagnostic Imaging; Equipment; Frequencies (time pattern); Human; human subject; Hybrids; Image; Image Reconstructions; imaging modality; Imaging problem; improved; in vivo; Ionizing radiation; Left; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Methodology; Methods; microwave electromagnetic radiation; Modality; Modeling; Monitor; Morphology; Nonionizing Radiation; Operating Rooms; Patients; Phase; portability; Process; Property; public health relevance; reconstruction; Research Methodology; research study; Research Technics; Resolution; Scanning; Signal Transduction; sound; Speed (motion); stroke; Techniques; Time; tomography; transmission process; tumor; Ultrasonic Therapy; Ultrasonics; Ultrasonography; Validation; X-Ray Computed Tomography
Relevance: The development of thermoacoustic tomography brain imaging will yield a powerful and effective new modality for monitoring brain conditions such as strokes, tumors, and brain injuries. Its specific advantages over existing high-resolution human brain imaging modalities include 1) relatively low-cost, 2) portability that would permit near real-time imaging studies at bedside or in operating rooms, 3) use of non-ionizing radiation, and 4) measurement of structural and functional brain information that is complementary to that revealed by existing methods
Project start date: 2010-04-01
Project end date: 2013-12-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-07-070
7R01EB010049-02 (2011): $408577
SENSORY BASED CNS DIAGNOSTICS FOR THE CLINIC
A Mark, Associate Professor
University Of North Carolina Chapel Hillcity: Chapel Hill country: United States (us)
Grant 1R21NS072811-01A1 from National Institute Of Neurological Disorders And Stroke
Abstract: There is currently a significant gap that exists between fundamental neuroscience research and translation of the findings of that research into everyday practice. Experimental findings at the genetic, cellular, molecular and systems level often take a fairly long and frequently circuitous route to make an impact on a particular neurological disease or disorder. The goal of our work is to bridge the neuroscientific gap at the systems level of study by developing standardized sensory measures that can be not only utilized in clinical or clinical research settings, but can be directly correlated with the observations obtained directly from sensory cortex in non-human primates via high resolution imaging and extracellular recording. Successful development of an experimental model that iteratively evaluates the relationship of clinical measures and systemic CNS responses to specific mechanistic alterations will be quite significant. Such an evaluation of an individual´s CNS status could be directly linked to systemic mechanistic deficiencies or alterations observed in animal experimentation. Towards that goal, we have successfully designed and fabricated a tactile sensory diagnostic device. In parallel with that development, we designed a number of protocols - based on experimental neurophysiological findings from both our non human primate research and that of others - that could be rapidly and efficiently delivered (1-3 minutes) to a number of subject populations. The tactile diagnostic system that we have developed was conceptually designed to investigate differences in cortical information processing strategies between people with autism and people without. In this proposal we ask whether or not the strategy that we have devised for investigating a population with a neurodevelopmental disorder could be broadly applied to a number of neurological disorders. In other words, we consider the changes manifested by the neurodevelpmental disorder autism to be systemic, and if systemic cortical alterations occur in other neurological disorders, could they also be detected in the same manner? Proof-of-concept studies in a number of clinical research areas demonstrated that these newly developed metrics were sensitive to systemic cortical alterations. One question that emerges from this data is that most of these neurological disorders result in some type of altered central sensitization, no matter what the cause - whether it be neurodevelopmental, neurodegenerative, pharmacological or trauma induced - in which there is a significant change in the balance between excitation and inhibition. This application proposes to determine if sensory perceptual metrics, similar to those that were used to successfully distinguish subjects with autism from healthy control populations (with 90% accuracy using SVM to assess the results of a 25 minute battery of 9 protocols), could be used to reliably distinguish - on an individual basis - subjects with neurological disorders that are not neurodevelopmental in nature. Towards this goal, we target subjects from one broad category of neurological disorders - chronic pain. More specifically, we will examine the differences and commonalities from observations of pain patients diagnosed with one of the following fibromyalgia, vulvodynia, TMJD, IBS and migraine. The overall goal of the proposed work is to investigate the utility of novel sensory-based methodologies that are currently being used in both basic and clinical research. Recently, utilizing state-of-the-art technology, we built a multi-site tactile stimulator that allows for investigation of central nervous system (CNS) health and advanced methods in sensory perceptual metrics. These metrics have been demonstrated to be sensitive to changes in centrally mediated mechanisms; and systemic alterations of cortical health (via neurodegenerational, neurodevelopmental, pharmacological or trauma induced changes) robustly change the measures. It is anticipated that clinicians will be able to utilize these measures to improve diagnostic performance and enable assessment of efficacy of treatment. The study itself will serve to validate the utility of a number of these measures in several types of pain, specifically fibromyalgia, TMJD, IBS, vulvodynia and migraine. The information from this study could aid in understanding centrally mediated mechanisms that undergo significant alterations with chronic pain
Keywords: Address; Age; analytical tool; Animal Experimentation; Area; Autistic Disorder; base; Basic Science; Behavior; Brain Concussion; Caregivers; Categories; central sensitization; Cerebrum; chronic pain; Clinic; Clinical; Clinical Research; cohort; cost effective; Data; data mining; Databases; demographics; design; Development; Devices; Dextromethorphan; Diagnosis; Diagnostic; Disease; Equilibrium; Evaluation; Experimental Models; extracellular; Fibromyalgia; GABA Agonists; gamma-Aminobutyric Acid; Genetic; Goals; Health; Image; improved; in vivo; Individual; information processing; Investigation; Laboratory Animals; Lead; Letters; Link; Machine Learning; Measures; Mediating; Methodology; Methods; Metric; Migraine; Molecular; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nature; Nerve Degeneration; nervous system disorder; Neuraxis; Neurodevelopmental Disorder; Neurons; neurophysiology; Neurosciences Research; neurotransmission; nonhuman primate; novel; Ophthalmic examination and evaluation; Pain; Patients; Performance; Physiological; Play; Population; Population Control; Primary Health Care; Process; process optimization; protocol development; Protocols documentation; Recruitment Activity; Research; Resolution; response; Role; Route; Sensory; sensory cortex; Site; Stimulus; System; Tactile; Techniques; Technology; Temporomandibular Joint Disorders; Testing; Translations; Trauma; Treatment Efficacy; United States National Institutes of Health; Vulvodynia; white matter damage; Work
Relevance: The overall goal of the proposed work is to investigate the utility of novel sensory-based methodologies that are currently being used in both basic and clinical research. Recently, utilizing state-of-the-art technology, we built a multi-site tactile stimulator that allows for investigation of central nervous system (CNS) health and advanced methods in sensory perceptual metrics. These metrics have been demonstrated to be sensitive to changes in centrally mediated mechanisms; and systemic alterations of cortical health (via neurodegenerational, neurodevelopmental, pharmacological or trauma induced changes) robustly change the measures. It is anticipated that clinicians will be able to utilize these measures to improve diagnostic performance and enable assessment of efficacy of treatment. The study itself will serve to validate the utility of a number of these measures in several types of pain, specifically fibromyalgia, TMJD, IBS, vulvodynia and migraine. The information from this study could aid in understanding centrally mediated mechanisms that undergo significant alterations with chronic pain
Project start date: 2011-07-01
Project end date: 2013-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-10-069
1R21NS072811-01A1 (2011): $218946
COMBINATION THERAPIES FOR CHRONIC HBV, LIVER DISEASE AND CANCER
A Mark, Dr.
Temple Universitycity: Philadelphia country: United States (us)
Grant 5R01AI076535-04 from National Institute Of Allergy And Infectious Diseases
Abstract: There are an estimated 350 million people worldwide who are chronically infected with hepatitis B virus (HBV) and are at high risk for the development of hepatitis, cirrhosis (end stage liver disease) and hepatocellular carcinoma (HCC). Hepatitis and cirrhosis are associated with prolonged morbidity, and HCC, which appears in more than 250,000 people each year, is rapidly fatal. Given that the major risk factors for HCC are the HBV carrier state (defined as the persistence of virus or virus antigens in blood for more than 6 months) and chronic liver disease (CLD) (hepatitis and cirrhosis), the most direct way to reduce risk factors for HCC is to target the virus and/or corresponding immunity. Accordingly, the FDA has now approved interferon 1, pegylated interferon 1, lamivudine, adefovir dipivoxal, entecavir, and telbivudine. Additional drugs, such as emtricitabine, clevudine, and tenofovir, will probably be approved soon. Although these are potent drugs, they are limited by low rates of sustained response, side effects, and the emergence of drug resistance. Hence, the objective of this proposal is to devise combination therapies, following the model of HIV combination therapy development, to successfully treat long term HBV infection. To do so, the lab will assess the pharmacokinetics (PK), antiviral efficacy and toxicity of drug combinations in primary human hepatocytes and in HepG2 cells replicating wild type or selected mutants of HBV (aim 1). Favorable combinations will then be assessed in vivo in nude mouse injected with HepAD38 cells (AD38 cells replicate wild type HBV, which accumulates in the blood of these mice) in order to get a sense of what combinations and concentrations of drugs are most effective in reducing virus titer, for assessing how long virus DNA levels remain suppressed during and after treatment, and whether different combinations have a favorable PK profile in vivo (aim 2). The best combinations will then be evaluated for long term antiviral efficacy in HBV transgenic SCID mice, which stably replicate wild type HBV and develop CLD (aim 3). This work will develop combination therapies that will demonstrate a sustained antiviral effect against HBV, against HBV in HIV co-infected patients, in chronically infected alcoholics, as well as prolonged suppression of CLD. Elimination of CLD will reduce the risk of chronic HBV carriers of developing HCC. This will contribute centrally to the design of future clinical trials that will be suitable for long term treatment of chronic infections without significant side effects or the frequent development of drug resistance that limit present day therapeutics against HBV. PUBLIC HEALTH RELEVANCE There are more than 350 million people worldwide chronically infected with hepatitis B virus (HBV) and who are at risk for the development of hepatitis (inflammation of the liver), cirrhosis, and liver cancer. Millions of people each year die from liver cirrhosis. Liver cancer is among the top five most prevalent tumor types worldwide, with an estimated 1 million deaths each year. Present treatments for chronic hepatitis B use single drugs that are expensive, have side effects, and select for drug resistant viruses. Hence, new therapeutic options to treat long term virus infection and associated diseases are urgently needed. The proposed work will develop combination therapies with sustained antiviral effect against HBV and associated chronic liver disease, against HBV in HIV co-infected patients, and against HBV among chronic alcoholics. Prevention and/or elimination of chronic liver disease will reduce the risk of HBV carriers developing cirrhosis and liver cancer, thereby contributing centrally to improving public health
Keywords: 2`-fluoro-5-methylarabinosyluracil; Address; adefovir; Adoptive Transfer; Adverse effects; Aftercare; analog; Animal Model; Antiviral Agents; Appearance; base; Biological Assay; Blood; Carrier State; Cell Line; Cells; Cessation of life; Characteristics; Chronic; Chronic Hepatitis B; Cirrhosis; Clinical; Clinical Trials; Combined Modality Therapy; Data; design; Development; Developmental Therapeutics Program; Disease; Disease remission; Drug Administration Routes; Drug Combinations; Drug Kinetics; Drug resistance; drug resistant virus; emtricitabine; entecavir; Extrahepatic; Future; Goals; Half-Life; HBV Liver Disease; Health; Hepatitis; Hepatitis B; Hepatitis B Virus; hepatitis B virus P protein; Hepatocyte; high risk; HIV; Human; Immune; Immunity; improved; In Vitro; in vivo; Infection; Inflammation; Interferons; Lamivudine; Liver Cirrhosis; Liver diseases; Malignant neoplasm of liver; Modeling; Morbidity - disease rate; Mus; mutant; novel therapeutics; nucleoside analog; Nude Mice; Organ; Pathogenesis; Patients; Pharmaceutical Preparations; Polymerase; Prevention; Primary carcinoma of the liver cells; problem drinker; Protocols documentation; public health medicine (field); Resolution; response; Risk; Risk Factors; SCID Mice; South Korea; Staging; Telbivudine; Tenofovir; Testing; Tetracycline Control; Therapeutic; therapy development; Toxic effect; Transgenic Organisms; tumor; uptake; Viral Antigens; viral DNA; Virus; Virus Diseases; Virus Replication; Work
Project start date: 2008-06-15
Project end date: 2013-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-07-070
5R01AI076535-04 (2011): $347054
GERIATRIC ACADEMIC LEADERSHIP AWARD
A Mark, Chief, Divison Of Geriatrics
University Of Utahcity: Salt Lake City country: United States (us)
Grant 5K07AG028403-05 from National Institute On Aging
Abstract: The University of Utah is preparing to meet the challenge of the demographic imperative of the aging population in Utah and the nation with a significant new commitment to support aging-related research programs through its expanded, interdisciplinary Center on Aging. This Geriatric Leadership Academic Award will allow Mark Supiano, M.D. to lead the development of an expanded aging-related research agenda for the University of Utah. Dr. Supiano holds major leadership positions in aging research and Geriatric Medicine within the University of Utah with his appointments as Professor of Internal Medicine and Chief of the Division of Geriatrics, Executive Director of the University of Utah Center on Aging, and Director of the Department of Veterans Affairs Salt Lake City Geriatric Research Education and Clinical Center (GRECC). In these positions, he will be able to direct this project, promote interdisciplinary collaborations, and enhance aging-related research program development across the University of Utah campus. The primary objective of this proposal to enhance the visibility and support for aging-related research at the University of Utah will be accomplished by achieving the following three specific aims. Specific Aim 1. Expand the number of investigators with aging-related research interests. The measurable goal for this aim is the increase in the number of investigators identified at the University of Utah with funded programs in aging-related research. The growth will occur through recruitment to four areas of research strength, developing new partnerships, and by career development. Specific Aim 2. Foster the development of new interdisciplinary collaborations in aging research. The Center will support an infrastructure to facilitate aging research by developing a registry for subject recruitment, providing administrative assistance, and developing a facility for exercise and rehabilitation protocols. Accomplishing this aim will be evaluated by the further development of the Center on Aging program, success of the pilot grant program, growth in the University´s aging research related grant portfolio, and funding for interdisciplinary research programs and center grant proposals. Specific Aim 3. Develop a multidisciplinarv research training program in aging for pre- and post-doctoral trainees. The measurable outcomes for this aim are the number of trainees who participate in aging-related research, the development of the aging-research curriculum in the K30 program, and funding for a multidisciplinary T32 training grant focused on aging research. Dr. Supiano will utilize the support requested from the Geriatric Leadership Academic Award to implement this plan to significantly enhance the aging-related research programs at the University of Utah
Keywords: age related; Aging; aging population; Applications Grants; Appointment; Area; Award; career development; Cities; Clinical; Clinical Research Curriculum Award; Clinical Services; Coenzyme A; Community Services; Complement; Continuity of Patient Care; Development; Doctor of Medicine; Educational aspects; Educational Curriculum; Elderly; Elements; Exercise; Faculty; Fostering; Foundations; Funding; Geriatrics; Gerontology; Goals; Grant; Growth; Health Sciences; Housing; Incentives; interdisciplinary collaboration; Interdisciplinary Study; interest; Internal Medicine; Investments; Lead; Leadership; Measurable; meetings; member; Mission; Modeling; multidisciplinary; older patient; Outcome; Outcome Measure; Patient Care; patient population; Penetration; Positioning Attribute; Postdoctoral Fellow; pre-doctoral; Process; professor; Program Development; programs; Protocols documentation; Registries; Rehabilitation therapy; Research; research and development; Research Infrastructure; Research Personnel; Research Project Grants; Research Training; Rewards; Sodium Chloride; Strategic Planning; success; Training; Training Programs; Universities; Utah; Veterans
Project start date: 2007-09-01
Project end date: 2012-05-31
Budget start date: 15-JUN-2011
Budget end date: 31-MAY-2012
5K07AG028403-05 (2011): $108000
Sponsored Links Excellgen http://Excellgen.com
A Mark, Professor
Vanderbilt Universitycity: Nashville country: United States (us)
Abstract: The Transgenic Mouse/ES Cell Shared Resource has been in existence since 1993 and has received continuous funding from the NCI since the Vanderbilt-lngram Cancer Center (VICC) was awarded its first Cancer Center Support Grant in 1995. At the time of the last competitive renewal, this shared resource received an "Outstanding" rating. This resource provides gene targeting, DNA pronuclear microinjections, ES cell microinjections, assisted reproduction and both sperm and embryo cryopreservation services to members of the VICC. These services are essential for the generation, maintenance, and long-term storage of germline-altered mice. The resource continues to function in a multidisciplinary manner and has undergone several significant changes since the last competitive evaluation that have enabled it to continue to provide gene targeting and microinjection services at reasonable prices, to develop several new services, and to improve both its quality control and data management strategies. The Transgenic Mouse/ES Cell Shared Resource continues to offer services that remain in high demand and vital to the generation of new mouse models of cancer and other diseases. This will be critical as the gene-specific information from genome-wide cancer studies is translated to mouse models of human cancer. Moreover, the technology base that this resource supports is expected to be important in allowing Vanderbilt investigators to adapt to using of human pluripotent stem cells in the future
Keywords: Age; Alleles; animal facility; Animals; antibiotic G 418; assisted reproduction; Award; base; blastocyst; Cancer Center; Cancer Center Support Grant; Cells; Collaborations; Complex; Consultations; Cryopreservation; data management; design; Disease; DNA; Electroporation; Embryo; embryo cell; Embryo Transfer; embryonic stem cell; Employee; Ensure; Evaluation; Fee-for-Service Plans; Female; Fertilization; Fertilization in Vitro; Freezing; Funding; fusion gene; Future; Ganciclovir; Gene Targeting; Generations; Genes; Genetic; genome-wide; Guidelines; Harvest; Human; human cancer mouse model; Human Resources; hygromycin A; Implant; improved; Individual; Knock-in Mouse; Leadership; Liquid substance; Maintenance; male; Malignant Neoplasms; member; Methods; Microinjections; Modification; Monitor; mouse genome; mouse model; multidisciplinary; Mus; Nitrogen; Outcome; Ovarian; Ovary; ovary transplantation; Partner in relationship; pathogen; Plasmids; Pluripotent Stem Cells; Policies; Preparation; prevent; Price; Principal Investigator; Procedures; Protocols documentation; pup; Puromycin; Quality Control; reconstitution; Research Personnel; research study; Resource Sharing; Resources; Risk; Schedule; Screening procedure; Services; Site-Directed Mutagenesis; Solid; Southern Blotting; sperm cell; Sterility; Techniques; Technology; Testing; The Jackson Laboratory; Time; Training; Transgenes; Transgenic Mice; Transgenic Organisms; Translating; Transplantation; vector; Vial device; web site; zygote
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
5P30CA068485-15_6305 (2011): $86878
PULSE WAVE VELOCITY AND CENTRAL AORTIC PRESSURE OUTCOMES IN SPRINT
A Mark, Chief, Divison Of Geriatrics
University Of Utahcity: Salt Lake City country: United States (us)
Grant 1R01HL107241-01A1 from National Heart, Lung, And Blood Institute
Abstract: The Systolic Blood Pressure Intervention Trial (SPRINT) affords a unique opportunity to determine if the difference in peripheral (brachial) systolic blood pressure (SBP) that will develop between the intensive treatment group (target SBP < 120 mm Hg) and the usual care group (target SBP < 140 mm Hg) will be accompanied by significant differences in measures of vascular stiffness (aortic pulse wave velocity, aPWV) and central (aortic) BP. The overall hypothesis addressed in this SPRINT ancillary study is that measures of vascular stiffness will be predictive of the main SPRINT outcomes independent of the achieved peripheral SBP. Three primary specific aims are proposed. Specific Aim 1 To determine if aPWV (and sub-aim 1, measures of central BP) in SPRINT study subjects randomized to the intensive treatment group at year three post-randomization will be lower compared to the usual care treatment group. Specific Aim 2 To determine if the aPWV (and sub-aim 2, measures of central BP) achieved (adjusted for baseline value) in SPRINT study subjects will be an independent predictor of the primary SPRINT outcomes (CV disease events) as well as all cause mortality, decline in renal function, rate of incident dementia and age-related cognitive decline. Specific Aim 3 To determine the associations at baseline between aPWV and central BP and relevant biomarkers of vascular aging and stiffness (fasting glucose, insulin, insulin sensitivity, hemoglobin A1C, and renin and aldosterone) and markers associated with chronic kidney disease (CKD - serum calcium, phosphorous, parathyroid hormone levels, uric acid and urinary albumin). This time-sensitive ancillary study to SPRINT will add important information regarding the underlying mechanisms for vascular stiffness by assessing clinically relevant biomarkers for glucose metabolism, insulin sensitivity, the renin-angiotensin-aldosterone system, and markers associated with CKD. In addition, by collecting baseline (at randomization) and longitudinal, annual measures of vascular stiffness (aPWV) and central aortic BP using a validated, reproducible, non-invasive methodology, the value of these measures with regard to the primary SPRINT clinical outcomes will be determined. No large scale studies have addressed whether reductions in vascular stiffness per se - independent of the fall in peripheral BP - provides a better predictor of clinical benefits. Moreover, no study has assessed the change in aPWV or central aortic BP in patients treated to a target SBP of 120 mm Hg. The addition of measures of vascular stiffness will help to determine if these outcomes should be considered as a therapeutic target over and above the peripheral BP achieved. The addition of aPWV and central aortic BP measures as well as several biomarkers of vascular stiffness in this SPRINT ancillary study are therefore important scientific additions to the parent trial. The age-associated increase in blood pressure combined with the world-wide demographic increase in the aging population means that hypertension represents an enormous emerging global public health concern. Vascular stiffness that develops with aging is a major contributor to the development of hypertension. This ancillary study to the Systolic Blood Pressure Intervention Trial (SPRINT) study will investigate potentially useful clinical measures and surrogate biomarkers of vascular stiffness to determine if measures of vascular stiffness should be should be considered as a therapeutic target over and above the reduced peripheral systolic blood pressure that will be achieved in the intensive treatment arm of the SPRINT study. (End of )
Keywords: Address; Age; Age-associated memory impairment; Aging; Albumins; Aldosterone; Ancillary Study; arm; Biological Preservation; biomarker; Blood Pressure; blood pressure regulation; Blood Vessels; Calcium; cardiovascular disorder risk; cardiovascular risk factor; Cardiovascular system; Chronic Kidney Failure; Clinic; Clinical; Clinical Trials Design; clinically relevant; cognitive function; cost effectiveness; Dementia; Disease; Event; falls; fasting glucose; follow-up; glucose metabolism; Goals; Hemoglobin; Hemoglobin concentration result; Hormones; Hypertension; Insulin; insulin sensitivity; interest; Intervention Trial; Living Costs; Measures; Methodology; Mortality Decline; Outcome; Parathyroid gland; Parents; Patients; Peripheral; peripheral blood; Phosphorous; Physiologic pulse; Population; Population Study; pressure; primary outcome; Quality of life; Randomized; Randomized Clinical Trials; Recruitment Activity; Renal function; Renin; Renin-Angiotensin-Aldosterone System; secondary outcome; Serum; Study Subject; Testing; therapeutic target; Time; treatment as usual; treatment program; Uric Acid; urinary
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: RFA-HL-10-024
1R01HL107241-01A1 (2011): $457454
PROGRAM OF EXCELLENCE IN SCIENTIFICALLY VALIDATED TREATMENTS OF MOOD DISORDERS
A Mark, Associate Professor
University Of Colorado At Bouldercity: Boulder country: United States (us)
Grant 5R25MH084774-04 from National Institute Of Mental Health
Abstract: The proposed research education program seeks to bridge the gap between science and practice of psychotherapy training through developing integrative curricula for training in core competencies required for scientifically-informed clinical practice (a) measurement and assessment, (b) intervention, and (c) evaluation. Evidence-based, scientifically-informed training based on these three core competencies will provide trainees with the skills necessary to develop and administer effective psychosocial treatments, train others in these treatments, and evaluate the impact of treatments, thereby advancing the science and practice of psychotherapy. Based on findings that mood disorders are among the most common and debilitating psychiatric conditions in the United States, and that people with mood disorders are often under-treated, the specific objectives of this project are to develop, evaluate, and disseminate curriculum materials for three empirically supported treatments for mood disorders cognitive therapy (CT) and behavioral activation (BA) for treating major depressive disorder, and family-focused therapy (FFT) for treating bipolar disorder. Through readings, slides and handouts, videotaped lectures and role-plays, and experiential exercises and supervision, the program seeks to more fully and seamlessly integrate training in scientific knowledge and clinical practice of psychotherapy. The materials will be targeted for the training of clinical psychology graduate students, although they should also be useful in training practitioners in other disciplines and other levels of experience. The impact of the education program will be evaluated in terms of research competence and clinical competence as assessed by standardized fidelity scales. A new website will be developed that will serve as a national clearinghouse for state-of-the-science training materials on CT, BA, and FFT, including the curriculum materials developed for this program. Because the research education program will emphasize training in the core competencies of assessment, intervention, and evaluation required for scientifically-informed psychotherapy, students who complete the program should not only have content expertise in administering a particular empirically supported treatment, but also be well equipped to meet the demands of accountability inherent in current clinical practice, and to train and supervise other clinicians, including clinicians who do not have training in empirically supported treatments. Furthermore, trainees should be well-prepared to advance the next generation of research on scientifically-validated treatments, thereby bridging the gap between the science and practice of psychosocial treatments for mood disorders. This project focuses on the development, evaluation, and dissemination of curricula for training clinical psychology graduate students in core competencies - assessment, intervention, and evaluation - required for scientifically-based clinical practice, with a focus on three empirically supported treatments for mood disorders (cognitive therapy, behavioral activation, family-focused therapy). Many graduate programs offer little or no training in empirically supported treatments, so the materials developed for the program will meet an important need in providing curriculum materials that more fully and seamlessly integrate science and practice in psychotherapy training. Evidence-based, scientifically-informed training based on these three competencies will provide trainees with skills necessary to develop and administer effective psychosocial treatments, train others in these treatments, and evaluate the impact of treatments, which should not only advance the science and practice of psychosocial treatments for mood disorders, but also have a positive effect on public health via improved mental health services
Keywords: Accountability; base; Bipolar Disorder; Clinical; Clinical Competence; clinical practice; Clinical Psychology; Cognitive Therapy; Competence; Development; Discipline; Educational aspects; Educational Curriculum; Educational workshop; Evaluation; evidence base; Exercise; experience; Family; FarGo; graduate student; Grant; improved; Intervention; Knowledge; lectures; Major Depressive Disorder; Measurement; Measures; meetings; Mental Depression; Mental disorders; Mental Health Services; Modeling; Mood Disorders; next generation; Play; programs; psychosocial; Psychotherapy; public health medicine (field); Reading; Research; Research Methodology; Role; Science; skills; Slide; sound; Students; Supervision; symposium; Training; United States; Videotape; web site
Project start date: 2008-09-30
Project end date: 2013-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: RFA-MH-08-080
5R25MH084774-04 (2011): $31398
A Mark, Professor
Washington Universitycity: Saint Louis country: United States (us)
Abstract: The proposed NTR Center will be led by Lihong Wang, PhD. He will be aided by the Administrative Core, which consists of four project/core leaders and an experienced research business director (Karen Monteiro Kharasch). This diverse group of leaders has been selected to represent a broad range of research interests and leadership expertise. These individuals make it realistic to manage an enterprise of this scope and magnitude. The Administrative Core will be led by Dr. Mintun. Drs. Mintun, Wang, Achilefu, Culver and Ms. Kharasch will review, facilitate and coordinate collaborations among all participants in the proposed NTR Center as well as interactions with other funded Centers within the NTR network. As Division Leaders of the Primary Project (Wang), Task-Specific Projects (Achilefu), Support Cores (Culver & Mintun) and Administrative Core (Mintun), each will facilitate communications back and forth between the Administrative Core members and the other team leaders. As experienced leaders of complex centers, all Administrative Core members realize the importance of clear and consistent communications
Keywords: Accounting; Advisory Committees; Award; Back; Budgets; Businesses; Cancer Center; Clinical Research; Collaborations; Communication; Complex; Contracts; Counseling; Development; Doctor of Philosophy; experience; Funding; Funding Opportunities; Grant; Individual; interest; Leadership; medical schools; member; Modification; operation; Optics; Participant; programs; Recommendation; Research; Research Infrastructure; Research Personnel; Sentinel Lymph Node; Services; Technology; Translational Research; Ultrasonography; working group
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
5U54CA136398-04_9001 (2011): $67120
CONTROLLING LARGE DNA FRAGMENTS DURING NANOPORE SEQUENCING
A Mark, Professor
University Of California Santa Cruzcity: Santa Cruz country: United States (us)
Grant 5RC2HG005553-02 from National Human Genome Research Institute
Abstract: The potential use of nanopores for DNA sequencing has gained significant momentum. This is partly due to innovative solid state techniques, but more so due to breakthroughs using biological pores. One promise of nanopore sequencing has been very long read lengths, however we and others have performed most of our experiments using short synthetic DNA oligomers. In this proposal, we present experiments designed to test how efficiently nanopores can control and process long DNA templates (up to 2500 nt in length) as they are catalytically modified by DNA polymerases. Our work will focus on T7 DNA polymerase (T7 DNApol) and the Klenow fragment of DNA polymerase I (KF), coupled to the alpha hemolysin biopore (1-HL). There are three aims Aim 1. Limit DNA replication to template strands captured one-by-one in the nanopore. To ensure efficient serial analysis of individual DNA templates during catalysis, we will optimize a new strategy developed in our laboratory that quantitatively blocks DNA replication in bulk phase buffer bathing the nanopore, and that activates replication of individual DNA templates exclusively at the nanopore. Aim 2. Quantify the effect of electrical force and DNA/pore interactions on DNA polymerase- dependent replication. Our objective is to determine the length of DNA template that can be reproducibly replicated on the nanopore. Three conditions (see figure below) will be examined to address three independent properties that could influence replication efficiency a) Polymerase replication of long DNA templates captured in the nanopore under no load; b) Polymerase dependent replication of long DNA templates against resistive forces that arise from DNA/pore interactions; c) Polymerase dependent replication against a resistive electrical force. Aim 3. Determine the effect of voltage on registry of large DNA templates in the nanopore at single nucleotide precision. Nanopore sequencing of intact DNA templates presupposes maintenance of single nucleotide spatial register during the time a base is read. For DNA-polymerase-controlled translocation this would be in the range of 1 to 100 milliseconds per measurement. At low voltages that are likely to permit polymerase catalysis, it is unclear if registry can be maintained. High speed DNA sequencing is fundamental to understanding human diseases including cancer and heart disease. This proposal addresses fundamental questions about one promising new DNA sequencing technique based on biological nanopores
Keywords: Address; akeson; base; Bathing; Biological; Buffers; Catalysis; Complex; Confidential Information; Coupled; design; Disclosure; DNA; DNA biosynthesis; DNA Polymerase I; DNA Sequence; DNA-Directed DNA Polymerase; Ensure; Freedom; Future; Heart Diseases; Hemolysin; human disease; Individual; innovation; Laboratories; Legal patent; Length; Maintenance; Malignant Neoplasms; Measurement; millisecond; nanopore; Nucleotides; Perch; Phase; Polymerase; Process; Property; public health relevance; Reading; Registries; Relative (related person); research study; Scheme; solid state; Speed (motion); synthetic construct; Techniques; Testing; Text; Time; time interval; United States; voltage; Work
Relevance: P.I. Akeson, M./ Deamer, D. PROJECTIVE NARRATIVE. High speed DNA sequencing is fundamental to understanding human diseases including cancer and heart disease. This proposal addresses fundamental questions about one promising new DNA sequencing technique based on biological nanopores
Project start date: 2009-09-22
Project end date: 2012-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2012
PFA/PA: RFA-OD-09-004
5RC2HG005553-02 (2010): $533470
COMBINING EXERCISE AND COGNITIVE TRAINING TO IMPROVE EVERYDAY FUNCTION
A Mark
Washington Universitycity: Saint Louis country: United States (us)
Grant 5R01AG034581-03 from National Institute On Aging
Abstract: The possibility that lifestyle activities may benefit cognitive health in late life is of major importance for our increasingly aging population. Although many studies of physical and cognitive training activities in older adults have attempted to demonstrate such benefits, transfer and maintenance of these benefits have been minimal. In this proposal, we introduce and evaluate two novel, theoretically motivated advances to optimize the effects of training, including transfer to daily, real world activities. Recognizing that real world activities, unlike laboratory tasks, rarely rely upon a single cognitive process, one advance is the incorporation of training that interleaves practice involving three cognitive control processes (task-coordination, prospective and retrospective memory). A second advance rests on the observation that few studies to date have carefully assessed the possibility that aerobic exercise and cognitive training together may be additive or synergistic in yielding cognitive benefits. Accordingly, an important objective is to evaluate the benefits of combining aerobic exercise with cognitive training for optimizing training and transfer of cognitive function, particularly for daily activities. We propose to conduct a randomized, controlled prospective study with residents of a Naturally Occurring Retirement Community (NORC). Ninety-six men and women, age 55-75 years who are in stable health and without contraindications to exercise or evidence of dementia or cognitive impairment, will be enrolled. Individuals will be randomly assigned to one of four groups for six months Exercise, Cognitive training, Combined exercise and cognitive training, and Control. This design will allow us to evaluate the unique benefits of each intervention for improving performance from baseline to post-training on measures of cognitive control, including training specific, laboratory and everyday transfer tasks; everyday subjective memory performance; self-reported activities of daily living (ADLs) and quality of life; and objective physical performance. We also plan to compare 6-month maintenance of transfer, ADL, and subjective memory performance gains for individuals in the Cognitive, Exercise, and Combined groups following the 6-month intervention period (12 months after baseline). The possibility that lifestyle activities may benefit cognitive health in late life is of major importance for our increasingly aging population. Although many studies of physical and cognitive training in older adults have attempted to demonstrate such benefits, transfer and maintenance of these benefits have been minimal. If cognitive training combined with aerobic exercise training is proven to have effects that transfer to everyday activities and are sustained, the results of this study could eventually be directly applied to a variety of community settings to reduce or delay age-related cognitive decline
Keywords: Activities of Daily Living; Address; Aerobic Exercise; Age; Age-associated memory impairment; aging population; base; Cognition; Cognitive; cognitive control; cognitive function; cognitive training; Communities; community setting; cooking; County; Dementia; design; Elderly; Enrollment; Exercise; flexibility; Fostering; Health; Impaired cognition; improved; Individual; Intervention; intervention effect; Laboratories; Life; Life Style; Maintenance; Marshal; Measures; Memory; memory retrieval; men; novel; Participant; Patient Self-Report; Performance; post intervention; Procedures; Process; prospective; prospective memory; Prospective Studies; Psychological Transfer; public health relevance; Quality of life; Randomized; Relative (related person); Reporting; Research; Rest; Retirement; Sampling; Training; Training Activity; Woman
Relevance: The possibility that lifestyle activities may benefit cognitive health in late life is of major importance for our increasingly aging population. Although many studies of physical and cognitive training in older adults have attempted to demonstrate such benefits, transfer and maintenance of these benefits have been minimal. If cognitive training combined with aerobic exercise training is proven to have effects that transfer to everyday activities and are sustained, the results of this study could eventually be directly applied to a variety of community settings to reduce or delay age-related cognitive decline
Project start date: 2009-09-15
Project end date: 2012-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
5R01AG034581-03 (2011): $242811
5R01AG034581-02 (2010): $252956
1R01AG034581-01 (2009): $257709
COMMUNICATIONS AND SAFETY MONITORING SYSTEM (COSMOS) FOR HOME-BASED ELDERLY CARE
A Mark
Gen-9, Inc.city: Mountain View country: United States (us)
Grant 1R43AG039159-01 from National Institute On Aging
Abstract: The population of the United States, as in most developed nations, is aging and is doing so at an increasing rate. This change in demographics is having a dramatic affect on the nation´s healthcare delivery system and the related public costs. Long-term home care for the elderly is a major component of this cost trend. It has been proposed that the quality of home care can be significantly improved and the cost, as well as the time burden to family caregivers, significantly reduce through the application of new assisted living technologies that supports the remote monitoring of the elderly patient´s activities, health and safety. This technology is expected to play a vital role in decreasing the cost and increasing the quality of elderly home-based care in the future. However, both the existing and more recently proposed assisted living technologies present one or more problems or limitations including being expensive and complex to install, use and maintain. This project presents a alternative approach called the Communications and Safety Monitoring System (CoSMoS). CoSMoS is intended to deliver comparably superior remote activity, health and safety monitoring, as well as communication functions, and do so at a much lower cost of installation, use and maintenance by integrating the best of breed network and hardware solutions available today. The CoSMoS platform will be an integrated hardware/software solution that is user-friendly, scalable and that will facilitate secure, non-intrusive communication and remote monitoring of elderly users by their caregivers, families and peers through a Web interface. The open and flexible nature of the CoSMoS platform will permit third parties, such a clinical researchers and medical device manufacturers, to develop new applications which can be easily and readily deployed over the same infrastructure thereby facilitating important applications and clinical research in the future. This project proposes to develop a new, low cost, ubiquitous and easy to use application, called CoSMoS, to support the independent living of the elderly. It will accomplish this by facilitating communication and interaction between them and their peers, caregivers, friends and family members while also providing information to caregivers with which to evaluate their health, safety or the need for intervention
Keywords: advanced age; Affect; Aged 65 and Over; Aging; Architecture; Area; assisted living; Assisted Living Facilities; assistive living; assistive living facilities; base; Behavior; body movement; Breeding; Care Givers; Care, Home; Caregivers; Caring; Characteristics; Clinical; Clinical Research; Clinical Study; Communication; Communication Aids for Disabled; Communication Aids for Handicapped; communication device; communication disorder aid; Complex; computer program/software; Computer Programs; Computer software; computerized data processing; cost; Data; Data Collection; data processing; Delivery of Health Care; demographics; Development; Devices; Elderly; elderly patient; Elderly, over 65; elders; Electronics; Engineering / Architecture; Environment; Family Care Giver; Family Caregiver; Family member; flexibility; Force of Gravity; Friends; Future; geriatric; Goals; Gravities; Health; health care delivery; Health Communication; Health Sciences, Allied and Health Services Delivery; Healthcare Delivery; Home; Home care of patient; Home environment; home for elderly; Home for seniors; Homecare of patient; Homes for the Aged; Household; improved; Independent Living; Infrastructure; Intervention; Intervention Strategies; interventional strategy; Investigators; late life; later life; Light; Location; Maintenance; Maintenances; Manufacturer; Manufacturer Name; Medical Device; meetings; Memory; Monitor; Movement; Nature; Network-based; Old Age Homes; older adult; older patient; older person; operation; patient home care; peer; performance tests; Phase; Photoradiation; Physical activity; Play; Population; Position; Positioning Attribute; programs; Programs (PT); Programs [Publication Type]; PROV; Provider; public health relevance; Research Infrastructure; Research Personnel; Researchers; Robot; robotic device; Role; Running; Safety; Secure; Senescence; senescent; senior citizen; sensor; Services; signal processing; social role; Software; software systems; solid state; Solutions; Speed; Speed (motion); System; System, LOINC Axis 4; Technology; Testing; Time; touch panel; touch screen; touch screen panel; touchscreen; touchscreen panel; Travel; trend; United States; user-friendly; Video Recording; video recording system; Videorecording; Voice; web interface; wireless; Wireless Technology; Work
Relevance: Narrative This project proposes to develop a new, low cost, ubiquitous and easy to use application, called CoSMoS, to support the independent living of the elderly. It will accomplish this by facilitating communication and interaction between them and their peers, caregivers, friends and family members while also providing information to caregivers with which to evaluate their health, safety or the need for intervention
Project start date: 2011-03-01
Project end date: 2011-08-31
Budget start date: 1-MAR-2011
Budget end date: 31-AUG-2011
PFA/PA: PA-10-050
1R43AG039159-01 (2011): $148500
A Mark, Professor
University Of California San Diegocity: La Jolla country: United States (us)
Grant 5R01GM043644-24 from National Institute Of General Medical Sciences
Abstract: The plant hormone auxin is involved in many, perhaps all, aspects of plant growth and development. Auxin acts by stimulating the degradation of a family of transcriptional repressors called the Aux/IAA proteins, a process that requires the ubiquitin protein ligase (E3) SCFTIR1. During the last grant period we showed that auxin binds directly to the F-box protein TIR1, the substrate binding subunit in an E3 called SCFTIR1. Auxin binding stabilizes the interaction between SCFTIR1 and the Aux/IAA proteins. This is a novel mechanism of both hormone perception and E3 regulation. In addition we showed that TIR1 binds an InsP6 molecule and suggest that InsP6 may be required for TIR1 structure and/or function. Further we demonstrated that TIR1 is one of 6 related auxin sensor F-box proteins, collectively called the AFBs. The current proposal has five specific aims. The first is to investigate the molecular mechanism of auxin perception by TIR1. Based on our previous work, we propose that auxin acts like molecular glue to stabilize the TIR1- Aux/IAA complex. Biochemical studies will be performed to test various aspects of this model. In addition, we will determine the importance of InsP6 for TIR1 function. The second Aim is to characterize the biochemical diversity of the AFB proteins. A series of in vitro studies will be performed to characterize auxin and Aux/IAA binding to each member of the family. The significance of any specific interactions will be determined in vivo. The third Aim is to identify and characterize protein complexes containing TIR1 and/or the Aux/IAA proteins IAA28 with the goal of obtaining further information on the regulation of TIR1. In addition, this aim will provide additional information on the specificity of TIR1 and Aux/IAA interactions and the cellular location of TIR1-Aux/IAA complex formation. Aim four is to determine the function of cyclophilin molecules in auxin action. The fifth Aim is to characterize the auxin transcriptional network with a focus on two transcription factors called ARF5 and ARF7. These studies address a number of key issues in cellular regulation and will have important implications for human health. The ubiquitin pathway and SCF E3s in particular, are involved in diverse disease processes including numerous cancers. Because SCFTIR1 is one of the best-characterized E3 complexes in any species, this work provides a unique opportunity to advance our understanding of this critical aspect of human disease Protein degradation by the ubiquitin/proteasome pathway is a central aspect of cellular regulation. Defects in the pathway contribute to many disease processes including cancers. This study will advance our understanding of the ubiquitin/proteasome pathway in cell function
Keywords: Address; Arabidopsis; Auxins; base; Binding (Molecular Function); Biochemical; Biochemical Genetics; Biological Process; cell growth regulation; Cell physiology; Comparative Study; Complex; Constitution; Cyclophilins; Defect; Disease; Evolution; F-Box Proteins; Family; Family member; Floor; Gene Targeting; Genetic; Genome; genome wide association study; Glues; Goals; Grant; Health; Hormones; Human; human disease; Hydrophobic Interactions; In Vitro; in vivo; insight; Location; Malignant Neoplasms; member; Modeling; Molecular; multicatalytic endopeptidase complex; novel; Pathway interactions; Perception; Phylogenetic Analysis; Physcomitrella; Plant Growth Regulators; plant growth/development; Plants; Process; Promotor (Genetics); protein complex; protein degradation; Proteins; receptor; Regulation; research study; Role; sensor; Series; Signal Transduction; Specificity; Structural Models; Structure; Testing; Tomatoes; Transcription Coactivator; transcription factor; Transcription Repressor/Corepressor; Ubiquitin; ubiquitin-protein ligase; Work
Relevance: Protein degradation by the ubiquitin/proteasome pathway is a central aspect of cellular regulation. Defects in the pathway contribute to many disease processes including cancers. This study will advance our understanding of the ubiquitin/proteasome pathway in cell function
Project start date: 1989-08-01
Project end date: 2013-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-07-070
5R01GM043644-24 (2011): $305032
Sponsored Links Excellgen http://Excellgen.com
5R01GM043644-23 (2010): $339366
CYTOSKELETAL REGULATION OF VESICLE TRANSPORT IN LIVER
A Mark, Professor And Chair
Mayo Cliniccity: Rochester country: United States (us)
Grant 5R37DK044650-20 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: The overall objective of this proposal is to define the molecular machinery that supports receptor-mediated vesicle trafficking processes in hepatocytes. These processes are essential for normal iron homeostasis, growth factor receptor signaling, and cell survival. Further, their disruption can lead to a variety of prevalent liver diseases. Here we focus on the vesicle-based machinery utilized by the hepatocyte at the plasma membrane (PM) and trans-Golgi network (TGN) to sort and traffic distinct receptors and cargo proteins. These include the transferrin receptors (TfRs), the epidermal growth factor receptor (EGFR), and lysosomal hydrolases used in their degradation. We have substantial preliminary data implicating the action of a conserved receptor sorting and vesicle formation machinery in hepatocytes that is centered around the membrane-severing GTPase dynamin 2 (Dyn2). We have found that this contractile polymer associates with the actin cytoskeleton and specific adaptor proteins at both the PM to regulate receptor endocytosis and the TGN to mediate trafficking of nascent hydrolases to the lysosome. Most recently, we have found that this complex can sort cargo through interactions with ubiquitin-associated proteins and is regulated by non- receptor tyrosine kinases. Thus, the CENTRAL HYPOTHESIS of this proposal is that a polymeric Dyn2 contractile scaffold associates with the actin cytoskeleton and specific adaptor proteins to mediate the dual processes of cargo sequestration and vesicle formation from the PM and TGN in hepatocytes. We will use state of the art imaging, biochemical, and molecular methods to explore three related but independent aims. In Aim One we will test how the regulated assembly of a Dyn2-actin endocytic complex mediates differential internalization and trafficking of the two different TfRs from the hepatocyte PM. In Aim Two we will define how the Dyn2 complex interacts with the ubiquitin-based sorting machinery in hepatocytes to mediate internalization and post-endocytic trafficking of the EGFR, targeting this receptor to lysosomes for degradation. Finally, in Aim Three we will define how the Dyn2 complex interacts with a novel ubiquitin-based sorting machinery at the hepatocyte TGN to maintain Golgi structure and mediate transport of newly synthesized hydrolases to the lysosome for EGFR degradation. This proposal is conceptually and technically innovative in that it provides major advances toward understanding the molecular mechanism of how essential hepatocyte receptors and cargo proteins are differentially sorted into vesicle carriers for subsequent trafficking to distinct organelles. The information gathered by these studies will help identify strategies for the treatment and prevention of diseases that affect basic liver function
Keywords: Actin-Binding Protein; Actins; Adaptor Signaling Protein; Affect; base; bile formation; Binding (Molecular Function); Biochemical; Capsid Proteins; Cell membrane; Cell Survival; Clathrin; Clathrin Adaptors; Complex; Cytoskeleton; Data; disorder prevention; Dissection; Dynamin; Dynamin 2; Endocytosis; Epidermal Growth Factor Receptor; Golgi Apparatus; Growth Factor Receptors; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Hepatocyte; Homeostasis; human EMS1 protein; Hydrolase; Image; information gathering; innovation; insight; Iron; Lead; Liver; Liver diseases; liver function; Lysosomes; Mediating; Membrane; Membrane Lipids; Methods; Molecular; Morphology; nexin; novel; Nutrient; Organelles; Play; Polymers; Process; protein complex; protein transport; Protein Tyrosine Kinase; Proteins; receptor; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Recycling; Regulation; Research Personnel; Role; scaffold; Sorting - Cell Movement; Structure; Tertiary Protein Structure; Testing; trafficking; trans-Golgi Network; Transferrin; Transferrin Receptor; Transport Vesicles; treatment strategy; Ubiquitin; Vesicle; Work
Project start date: 1992-02-01
Project end date: 2012-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5R37DK044650-20 (2011): $264923
NMR STUDIES OF PROTEIN SIDE-CHAIN DYNAMICS
A Mark
University Of Cincinnaticity: Cincinnati country: United States (us)
Grant 5R01GM063855-07 from National Institute Of General Medical Sciences
Abstract: The overall goal of this project is to investigate the contribution of amino acid side-chain dynamics to the physico-chemical mechanisms that determine the thermodynamics of recognition and association in protein/DNA interactions and the molecular basis of cooperativity of ion binding in calcium-binding proteins (CaBPs). Side chains can make significant contributions to the configurational entropy of a protein, thereby modulating the thermodynamics of protein function. A fundamental understanding of how proteins work therefore requires an intimate knowledge of the dynamic properties of the side chains. Two model systems, protein/DNA complexes and the CaBP calbindin D9k, have been selected for study that will allow key insights to be obtained regarding the role of side-chain dynamics in protein/DNA binding/recognition and cooperativity of ion binding, respectively. Despite the large number of structural and thermodynamic studies that have been reported for a variety of protein/DNA systems, critical and substantial gaps exist in our knowledge and understanding of the role played by molecular dynamics in protein/DNA interactions. A general problem in the field of molecular recognition is that structural studies reveal relatively little about the entropic component of the free energy of complex formation. Thus, it is very important to complement structural information by undertaking studies to investigate side-chain dynamics in the protein/DNA interface. Cooperative ion binding is one of the fundamental properties of calcium signaling pathways. The readout of intracellular calcium signals must be very finely tuned to effect a rapid response to the transient and subtle variations in Ca2+ concentrations that constitute the calcium signals. The great importance of cooperative binding of Ca2+ by EF-hand CaBPs has motivated efforts to determine the molecular basis for cooperativity in specific members of this protein family. Calbindin D9k, a single domain EF-hand CaBP, is one of the primary model systems for studying the cooperative binding phenomenon. The general hypotheses of the proposed research are that modulation of protein side-chain dynamics plays important roles in establishing a complementary interface between consensus/non-consensus DNA sequences and a cognate DNA-binding protein, and in promoting allosteric communication between ion-binding sites that leads to cooperative calcium binding. To test these hypotheses the following specific aims are proposed (1) determine the side-chain dynamics and thermodynamic properties of the K50-class homeodomains from the human Pitx2 and the Drosophila Bicoid proteins, bound to a consensus duplex DNA site; (2) determine the structure, dynamics and thermodynamics of the Pitx2 and Bicoid homeodomains bound to non-consensus DNA sites; (3) investigate the molecular basis and driving forces for cooperative binding of Ca2+ by the CaBP calbindin D9k; and (4) characterize the thermodynamic role of side-chain dynamics in the single-strand DNA-binding family of Telomere End Protection (TEP) proteins. The proposed research focuses on improving our understanding of two fundamental, biological processes that are critical for cellular function protein/DNA binding/recognition and cooperative ion binding. Protein/DNA complexes are of particular interest because an understanding of the principles guiding binding and recognition could suggest innovative solutions to a number of medical and biological problems that are associated with the regulation of DNA transcription; fundamental cellular activities such as the transcription, replication, recombination and repair of genes require the non-covalent interaction of DNA and DNA-binding proteins. Cooperativity is a fundamentally important functional property of biological systems such as the family of calcium binding proteins; calcium regulates a wide variety of cellular processes, such as muscle contraction, cell-cycle control, differentiation and signal transduction, and thus plays an essential role in human health
Keywords: Affinity; Amino Acids; base; Binding (Molecular Function); Binding Proteins; Binding Sites; Biochemical; Biological; Biological Models; Biological Process; biological systems; calbindin; Calcium; Calcium Binding; Calcium ion; Calcium Signaling; Calcium-Binding Proteins; Cell Cycle Regulation; Cell physiology; Chemicals; Communication; Complement; Complex; Consensus; Consensus Sequence; cooperative study; DNA; DNA Binding; DNA Sequence; DNA-Binding Proteins; DNA-Protein Interaction; driving force; Drosophila bicoid protein; EF Hand Motifs; EF-Hand Domain; Entropy; Exhibits; Family; Free Energy; Genes; Genetic Transcription; Goals; Health; homeodomain; Homeodomain Proteins; Human; Immobilization; improved; innovation; insight; interest; Ions; Knowledge; Lysine; Mediating; Medical; member; Modeling; Molecular; molecular dynamics; molecular recognition; Muscle Contraction; Play; Positioning Attribute; Property; Protein Binding; Protein Family; protein folding; protein function; Proteins; recombinational repair; Regulation; Reporting; Research; Research Design; research study; response; Rieger syndrome; Role; Side; Signal Pathway; Signal Transduction; Single-Stranded DNA; Site; Solutions; Specificity; SS DNA BP; Structure; System; Techniques; telomere; Testing; Thermodynamics; Variant; Work
Relevance: The proposed research focuses on improving our understanding of two fundamental, biological processes that are critical for cellular function: protein/DNA binding/recognition and cooperative ion binding. Protein/DNA complexes are of particular interest because an understanding of the principles guiding binding and recognition could suggest innovative solutions to a number of medical and biological problems that are associated with the regulation of DNA transcription; fundamental cellular activities such as the transcription, replication, recombination and repair of genes require the non-covalent interaction of DNA and DNA-binding proteins. Cooperativity is a fundamentally important functional property of biological systems such as the family of calcium binding proteins; calcium regulates a wide variety of cellular processes, such as muscle contraction, cell-cycle control, differentiation and signal transduction, and thus plays an essential role in human health
Project start date: 2003-05-01
Project end date: 2013-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-07-070
5R01GM063855-07 (2011): $332248
A Mark, Eminent Scholar
University Of Floridacity: Gainesville country: United States (us)
Abstract: The overall goal of this P01 application is to continue address of the hypothesis that antigen presenting cells (dendritic cells, macrophage/monocytes), through their interaction with components of the cellular immune system (NK T-cells, regulatory T cells), form a critical facet for the immune dysregulation which results in type 1 diabetes. This P01 renewal will examine this hypothesis with three separate but highly interactive Projects and will be supported by two well-established Core facilities (A-Administration; B-Pathology & Immunology). The Program requires an effective Administrative Core component as a central element of fiscal and scientific coordination. The four goals of Core A are as follows 1) To coordinate the budgetary and fiscal aspects of the Program. The proposed Program involves direct cost disbursements to investigators of the three Projects and two Cores; hence careful oversight represents an absolute administrative requirement. 2) To facilitate communication among investigators within the Program. This will take form through performance of many functions ranging from regularly scheduled meetings between Program investigators to training of Project Investigators by Program Cores. 3) To coordinate the goals and activities of the PO1 as a Program Executive Committee and respond to input provided by an External Advisory Committee, both for the purpose of maximizing the progress and success of the Program These committees will meet on a regularly scheduled basis and provide counsel to the Program Investigators regarding their program and recommendations for improvement. 4) To organize the collection of human materials, generate appropriate data sets, provide statistical support to the Program, assure compliance with appropriate regulatory bodies and edicts (e.g., IRB, IACUC, Health Insurance Portability and Accountability Act, etc.) and facilitate communication of Program results. In addition to the aforementioned functions, the administrative staff of the Program will also be responsible for communication with the NIH staff, for assistance with publications and presentation of Program results. The successful completion of these P01 studies should prove beneficial to improving our understanding of those events critical to the pathogenesis and natural history of type 1 diabetes, identifying markers that enhance our ability to monitor cellular immune activities in the disease, and developing immunotherapies capable of preventing or reversing the disorder
Keywords: Address; Advisory Committees; Antigen-Presenting Cells; base; Collection; Communication; Communication Programs; Core Facility; Counseling; Data Set; Dendritic Cells; Direct Costs; Disease; Elements; Event; experience; Goals; Health Insurance Portability and Accountability Act; Human; IACUC; Immune; immune function; Immune system; Immunology; Immunotherapy; improved; Institutional Review Boards; Insulin-Dependent Diabetes Mellitus; macrophage; meetings; Monitor; monocyte; Natural History; Pathogenesis; Pathology; Performance; prevent; Program Effectiveness; programs; Publications; Recommendation; Regulatory T-Lymphocyte; Research Personnel; Schedule; success; T-Lymphocyte; training project; United States National Institutes of Health
Project start date: 2011-09-01
Project end date: 2012-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
5P01AI042288-14_9004 (2011): $129882
5P01AI042288-13_9004 (2010): $122558
A Mark, Professor
Stanford Universitycity: Stanford country: United States (us)
Abstract: The NCBO encompasses numerous activities, projects, and sites. Our Center allocates substantial resources to scholarly and technical research and development as well as to collaborative Driving Biological Projects (DBPs), training, and dissemination activities. Consequently, the NCBO requires a comprehensive management structure that efficiently copes with complex administrative task of running a unified and interactive center
Keywords: Automobile Driving; Biological; biomedical informatics; biomedical ontology; Collaborations; Complex; Computational Biology; coping; Funding Opportunities; Future; Goals; Individual; Monitor; Process; research and development; Research Infrastructure; Research Personnel; Resources; Running; Site; Structure; training project; United States National Institutes of Health
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
5U54HG004028-07_8465 (2011): $397230
A Mark, Professor
Stanford Universitycity: Stanford country: United States (us)
Abstract: The NCBO creates tools and services that provide the ontological backbone for a broad range of scientific disciplines. We are producing a scalable, distributed infrastructure for publishing, managing, and evaluating ontologies. We are also creating ontology-based annotations of biomedical data sources to advance biomedical, clinical, and translational research. In the next five years, we will continue to grow the BioPortal library and services that will enable scientists to custom-tailor library components and to embed these components directly in their applications. The first generation of BioPortal focused on the content and services for the bio-ontology community. The next generation will provide additional content and services for the broader community of biomedical, clinical, and translational researchers, with an emphasis on generalizability and wide-scale adoption. In many cases, the ontology needs of a research area evolve quickly and researchers must be able to add new ontology terms and to refine and extend existing ones in order to meet community and institutional requirements. Our goal is to enable "agile ontology development"¿the incremental, user-guided, needs-driven evolution of ontologies. To accomplish this goal, we will integrate the infrastructure for ontology publishing, review, and application with the ontology-revision process, to create a common infrastructure for user feedback, change proposals, and updates by developers. We will use the annotation tools that we have already developed to annotate automatically a large set of public biomedical resources, creating a comprehensive index of ontology-based annotations for enabling translational discoveries. Finally, we will develop analytic methods to profile biomedical data sets for enrichment against the background of these annotations. As a result, just as biologists use the Gene Ontology to determine biological processes over-represented (or enriched) in a set of differentially expressed genes, clinical and translational investigators will be able to determine enrichment of terms representing diseases (or class of diseases), drugs, or other controlled terms in data sets of their choice
Keywords: Address; Adoption; Area; base; Biological Process; biomedical ontology; Biomedical Research; biomedical resource; Clinical; Clinical Research; Communities; Computer software; Custom; data format; Data Set; Data Sources; Databases; Development; Discipline; Disease; Evolution; Feedback; Generations; Genes; Goals; indexing; Libraries; Library Services; Maps; meetings; Methods; next generation; Nucleic Acids; Ontology; Peer Review; Pharmaceutical Preparations; Process; Publishing; Publishing Peer Reviews; Records; Research; Research Infrastructure; Research Personnel; Resources; Scientist; Services; tool; Translational Research; Update; Vertebral column; Work
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
5U54HG004028-07_8460 (2011): $1794623
THE ROLE OF MICROENVIRONMENT IN AGING-RELATED PHENOTYPES OF BREAST
A Mark, Staff Scientist
University Of Calif-lawrenc Berkeley Labcity: Berkeley country: United States (us)
Grant 5R00AG033176-03 from National Institute On Aging
Abstract: The mechanisms underlying the exponentially increased incidence of breast cancer in women >55 years of age are poorly understood. A useful conceptual framework from which to build hypotheses is that agingrelated phenotypes are etiologically rooted in changes In tissue-specific stem cells or in their regulation. Indeed, common aging-related phenotypes i.e. cancers and deficits in tissue regeneration both have been linked to stem cells. A number of reports that studied stem cells as a function of age have suggested that age-related phenotypes can be due to stem cell-intrinsic or-extrinsic factors, but that delineation appears to be tissue specific. The Bissell laboratory and others have shown that the mammary microenvironment is as important as are the mutations in epithelial tumor cells for development of breast cancers. In a number of cases it has even been shown that the microenvironment can be dominant over strong oncogenes. In the aging breast, does the microenvironment change so as to catalyze tumorigenesis? Do damaged or aged mammary stem cells cease listening to, or misinterpret regulatory cues from their microenvironment? Or is it a combination? We are now uniquely poised to address these questions for the breast. Over several decades, 3-dimensional culture models that mimic many aspects ofthe human mammary gland and breast cancer microenvironments were developed in the Bissell laboratory. Recently, we also have developed a cell-based microenvironment microarray technology that facilitates elucidation of the functional roles that are played by individual microenvironmental constituents and combinations thereof. We have used these models together with primary human mammary progenitor cells to demonstrate that the microenvironment can dictate mammary progenitor cell fate decisions. Here we propose to combine these assets to address the following specific aims (1) To identify age-dependent functional responses in microenvironment-directed mammary progenitor cell regulation, and the genetic circuitry that underlies them. (2) To determine whether mutations characteristic of breast cancers endow normal mammary progenitor cells with tumor-forming potential, or shifts their spectrum of response to mammary microenvironments in an age-dependent manner. (3) To design and test a therapeutic strategy based on age-related differences in mammary microenvironments and stem cell behavior using physiologically relevant 3D organotypic assays
Keywords: 3-Dimensional; Address; adult stem cell; Affect; Age; age related; Age-Years; aged; Aging; Aging-Related Process; base; Biological Assay; Breast; cancer risk; cell behavior; Cell physiology; Cells; Characteristics; Cues; design; Development; Epithelial; Gene Expression; Genetic; Human; Incidence; Individual; Laboratories; Link; malignant breast neoplasm; Malignant Neoplasms; Mammary gland; Microarray Analysis; Modeling; Mutation; Natural regeneration; neoplastic cell; Oncogenes; Phenotype; Plant Roots; Play; Regulation; Reporting; response; Role; Stem cells; Testing; Therapeutic; tissue regeneration; Tissues; tumor; tumorigenesis; Woman
Relevance: As we age the risk of cancer rises and our body´s tissues regenerate less efficiently; these characteristics of aging could be explained by dysregulated adult stem cells that othenA/ise maintain the affected tissues. Every cell resides in a so called ´microenvironment´, which is known to direct cellular functions, and is known to change during the aging process. Here we are exploring how age-associated changes to the breast microenvironment and to gene expression could conspire to misdirect mammary stem cells to generate tumors
Project start date: 2010-05-15
Project end date: 2013-04-30
Budget start date: 15-JUN-2011
Budget end date: 30-APR-2012
PFA/PA: PA-09-036
5R00AG033176-03 (2011): $232803
OPTIMIZATION OF PROCESSIVE ENZYMES FOR DNA SEQUENCING USING NANOPORES
A Mark, Professor
University Of California Santa Cruzcity: Santa Cruz country: United States (us)
Grant 1R01HG006321-01 from National Human Genome Research Institute
Abstract: The long-term objective of this project is rapid, highly accurate, and inexpensive sequencing of long (up to 150 kb) single DNA strands with a nanopore based DNA sequencing device. Meeting this long-term objective requires precise control of DNA movement past a nanopore sequence detector, and improvement of nanopore sequence detector resolution between DNA bases. The specific aims of this proposal build upon progress made to date in these two areas by laboratories at the University of California, Santa Cruz (Akeson), University of Washington (Gundlach) and the University of Pennsylvania (Drndic). Individual laboratory expertise and knowledge will be integrated to accomplish four specific aims. Specific aim one extends promising results at UCSC with DNA polymerase Phi29, a "molecular step motor" able to precisely control DNA movement through a nanopore sequencer. This work will employ existing personnel and 12 years of success at UCSC with alpha hemolysin protein nanopores to extend understanding of Phi29 DNA polymerase function in a nanopore. Specific aim two evaluates Phi29 DNA polymerase function with two nanopores selected for their potentially superior base resolution to the alpha hemolysin nanopore. The first is MspA, a protein nanopore, which will be evaluated with Phi29 DNA polymerase by U of Washington and UCSC teams. This collaboration takes advantage of expertise with use of Phi29 DNAP at UCSC and expertise with MspA at U of Washington. The second nanopore, a solid state ultrathin silicon nitride pore with fluorescence detection, will be evaluated with Phi29 DNA polymerase by U of Penn (makers of the solid-state nanopore) and UCSC teams. The third specific aim improves DNA base resolution through increased differences in current signals from individual bases. This will be achieved by increased salt concentrations in the nanopore combined with use of salt tolerant DNA Polymerases. DNA polymerases from salt tolerant organisms will be isolated by extremophile experts currently at UCSC. Specific aim 4 will use all information gathered to generate proof of concept through sequencing of long (up to 48 KB) DNA strands using a nanopore sequencing device. Realization of this technology will provide the basis for a more complete understanding of individual genetic traits and predispositions in human and other populations. This proposal develops nanopore based DNA sequencing for significant improvement in speed and fidelity of DNA sequencing over current technologies. The ultimate goal is sufficient speed and cost reduction to permit routine sequencing of individual genomes and ultimately provide the basis for a detailed understanding of individual genetic traits and predispositions. This understanding and technology are needed for personalized medicine in the 21st century
Keywords: active control; akeson; Area; Back; base; Biological; California; Centromere; Collaborations; cost; Cytosine; Detection; detector; Devices; dinitroaminophenol; DNA; DNA amplification; DNA biosynthesis; DNA Sequence; DNA-Directed DNA Polymerase; Engineering; Environment; Enzymes; Epigenetic Process; Excision; Fluorescence; Genetic; Genome; Genomics; Goals; Hemolysin; Human; Human Resources; improved; Individual; information gathering; innovation; Knowledge; Laboratories; Length; Medicine; meetings; Membrane; Methods; Methylation; Modification; Molecular; Motion; Motor; Movement; nanopore; Noise; novel; Nucleotides; Organism; Pennsylvania; Polymerase; Population; Predisposition; Proteins; Reading; Research; research study; Resistance; Resolution; Saline; sensor; Signal Transduction; silicon nitride; Single-Stranded DNA; Sodium Chloride; solid state; Solutions; Speed (motion); Staging; Structure; success; Technology; Testing; Thick; Time; trait; Universities; Viral; viral DNA; Washington; Work
Relevance: This proposal develops nanopore based DNA sequencing for significant improvement in speed and fidelity of DNA sequencing over current technologies. The ultimate goal is sufficient speed and cost reduction to permit routine sequencing of individual genomes and ultimately provide the basis for a detailed understanding of individual genetic traits and predispositions. This understanding and technology are needed for personalized medicine in the 21st century
Project start date: 2011-08-15
Project end date: 2014-07-31
Budget start date: 15-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: RFA-HG-10-012
1R01HG006321-01 (2011): $1291717
ADAPTIVE EXPERIMENTAL METHODS FOR EVALUATING COMPUTATIONAL MODELS OF COGNITION
A Mark
Ohio State Universitycity: Columbus country: United States (us)
Grant 5R01MH093838-02 from National Institute Of Mental Health
Abstract: The long-term goal of this program of research is to improve scientific inference in psychological science. The topic is investigated in the context of computational models of cognition, which can be extremely difficult to distinguish experimentally because of their complexity and the extent to which they mimic each other. Statistical methods (goodness-of-fit, Akaike Information Criterion) have been the dominant means of model evaluation and selection, and are applied after data have been collected in an experiment. The current project explores a new approach to improving inference by developing corresponding statistical methods that are applied on the front-end of an experiment, while the experiment is being designed. In this approach, dubbed adaptive design optimization (ADO), an experiment is divided into a series of mini-experiments. The design of each mini-experiment is updated based on performance in the preceding mini-experiment. The choice of design values is dictated by a sophisticated search algorithm that constantly pressures the models of interest to fit more and more challenging data points until one model emerges as superior. The adaptive nature of the methodology ensures the design is optimal throughout the testing session, and thereby maximizes the informativeness of the experimental results. Furthermore, the focus on optimizing the design simultaneously ensures that the experiment is highly efficient (e.g., fewer trials and participants). The three specific aims of the proposal are to (1) develop ADO so that it is applicable to a broad range of problems (e.g., various experimental designs, different modeling goals) in the discipline; (2) improve the ADO algorithm so that it can be used in real-time experiments; (3) develop web-based resources to enable researchers to learn about and take advantage of the methodology. The achievement of these three goals is intended to provide researchers with a new technology that can accelerate scientific discovery. Experimentation is one backbone of public health research. The research methodology to be developed in this application has the potential to increase simultaneously the efficiency of experimentation (thereby reducing the cost of doing science) and the informativeness of what is learned (thereby accelerating the advancement of science)
Keywords: Achievement; Address; Adoption; Age; Algorithms; Awareness; Back; base; Behavioral; Behavioral Sciences; Cognition; Cognitive; Cognitive Science; Computer Simulation; cost; Data; design; Development; Discipline; Discrimination (Psychology); Ensure; Episodic memory; Evaluation; Experimental Designs; Experimental Models; Feedback; Goals; Health Sciences; improved; infancy; interest; Language Development; Learning; Likelihood Functions; Maintenance; Memory; Methodology; Methods; Modeling; models and simulation; Nature; new technology; novel strategies; Online Systems; Participant; Perceptual learning; Performance; pressure; Process; programs; psychologic; public health relevance; public health research; Research; Research Methodology; Research Personnel; research study; Resources; Retrieval; Science; Series; sound; Speed (motion); Staging; Statistical Methods; Testing; Time; Update; Vertebral column; web site; Work
Relevance: Public Health Relevance Statement Experimentation is one backbone of public health research. The research methodology to be developed in this proposal has the potential to increase simultaneously the efficiency of experimentation (thereby reducing the cost of doing science) and the informativeness of what is learned (thereby accelerating the advancement of science)
Project start date: 2011-04-01
Project end date: 2016-01-31
Budget start date: 1-FEB-2012
Budget end date: 31-JAN-2013
5R01MH093838-02 (2012): $335788
Sponsored Links Excellgen http://Excellgen.com