DRUG-INDUCED ATM READTHROUGH OF PTC MUTATIONS
A Richard, Professor
University Of California Los Angelescity: Los Angeles country: United States (us)
Grant 5R01NS052528-05 from National Institute Of Neurological Disorders And Stroke
Abstract: This project stems from our long-standing goal to treat ATM deficiency, whether this be in cancer patients or in those suffering from ataxia-telangiectasia (A-T), a rare neurodegenerative disorder of children for which no treatment exists. Recently, we have obtained exciting evidence that certain antibiotic aminoglycosides, such as gentamicin and geneticin, induce the readthrough of premature termination codon (PTC) mutations in the ATM gene. The resulting ATM protein is functional, in that it corrects the radiosensitivity of A-T cells, phosphorylates ATM targets, and partially restores the S phase checkpoint, as demonstrated by measurement of radioresistant DNA synthesis. There is reason to believe that during the development of antibiotic aminoglycosides, over the past 40 years, many compounds were developed and screened for antimicrobial activity but not for PTC readthrough ability. High throughput screening will be developed, using assays based on protein truncation testing, to screen for new readthrough drugs. Promising compounds will then be further evaluated in secondary cell-based assays for ATM function, using mutations and cell lines that correspond to patient mutations. Tertiary testing will investigate the readthrough efficiency of various stop codons and the effect of the +4 nucleotide of each termination codon. Aminoglycoside-induced readthrough will be tested in combination with ATM promoter inducers in an effort to further boost intracellular ATM levels. A mouse model carrying a PTC mutation in the ATM gene will be generated for animal testing of selected drugs. Biomarkers will be developed for following in vivo responses to aminoglycoside treatment. These efforts are encouraged by the rationale that ATM heterozygotes live essentially normal lives with less than 50 percent of normal ATM protein levels. Furthermore, a subset of A-T patients with <15 percent of normal ATM protein tends to manifest less severe disease. These studies may impact upon other genetic disorders as well, and upon cancer patients with low levels of ATM protein
Keywords: A Mouse; Aminoglycoside Antibiotics; Aminoglycosides; Animal Model; Animal Testing; Animals; antimicrobial; Ataxia Telangiectasia; ataxia telangiectasia mutated protein; ATM function; ATM gene; ATM Gene Mutation; ATM promoter; base; Biological Assay; biomarker; Cancer Patient; Cell Line; Cells; Characteristics; Chemical Structure; Child; Clinical; Clinical Trials; design; Development; Diagnostic tests; Disease; DNA biosynthesis; Drug or chemical Tissue Distribution; Geneticin; Gentamicins; Goals; Hereditary Disease; Heterozygote; high throughput screening; improved; in vivo; Laboratories; Life; Measurement; Monitor; mouse model; Mutation; Neurodegenerative Disorders; Nonsense Codon; Nonsense Mutation; Nucleotides; Other Genetics; Patients; Pharmaceutical Preparations; Protein Truncation; Radiation Tolerance; Reading; Research; Residual state; response; restoration; S Phase; small molecule libraries; stem; T-Lymphocyte; Terminator Codon; Testing; Tissue Sample; tool; Toxic effect
Project start date: 2007-09-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5R01NS052528-05 (2011): $330138
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to A Richard
WNT PATHWAY REGULATION OF LENS POLARITY
A Richard, Emma & Irving Goldman Scholar
Children´s Hospital Med Ctr (cincinnati)city: Cincinnati country: United States (us)
Grant 2R01EY016241-06 from National Eye Institute
Abstract: Wnt pathways in lens polarity Wnt pathways are known to have a critical role in many aspects of development and disease. The long term goal of this competitive renewal application is an understanding of the role of Wnt pathways in regulating the epithelial to fiber cell transition and lens polarity during development. Preliminary studies show that when production of Wnt ligands is eliminated in the lens lineage, remarkably, lens epithelial cells differentiate into lens fiber cells. By contrast, when the Wnt pathway transcription factor Tcf3 is deleted conditionally in early lens, there is an opposite response where fiber cells fail to differentiate. These are surprising findings that underscore the importance of the Wnt/2-catenin pathway for regulating lens development and establishing the anterior epithelium-posterior fiber cell pattern that defines lens polarity. The function of this pathway in lens development has important implications for lens biology and perhaps for pathophysiologies where the epithelium is not maintained. Our central hypothesis is that The Wnt/2-catenin pathway regulates the epithelial-to-fiber cell transition to establish lens polarity. To investigate the validity of this hypothesis, we propose three Aims. 1. To determine the source of Wnt ligands crucial for establishing lens polarity. The mouse Wntless allele we have generated is very valuable because it is required for the activity of all Wnt ligands and thus solves the problem of how to generate a ligand loss-of-function when multiple ligands are expressed. We will take advantage of this allele, combined with different cre recombinase lines, to identify the source, or sources of Wnt ligands critical for the epithelial-to-fiber cell transition and lens polarity. 2. To determine whether non-canonical Wnt ligands provide negative-feedback regulation of the lens epithelial Wnt response. It has recently been shown that some Wnt ligands function only in the non-canonical pathways and furthermore, that they can block Wnt/2-catenin signaling by preventing the association of the Lrp5/6 co-receptors with Frizzleds. When coupled with the observation that several non-canonical ligands are expressed in lens fiber cells, this suggests that they may serve to down-regulate Wnt/2-catenin signaling after fiber cells have made contact with the epithelium. 3 To determine whether lens repolarization requires reactivation of the canonical Wnt pathway. In 1963, Coulombre and Coulombre performed the now classical experiment showing that a reversed chick lens (epithelium facing the retina) would re-polarize over the course of 10 days. As shown in our preliminary data, disruption of the Wnt pathway disrupts lens polarity suggesting that the Wnt pathway may be re-activated during re-polarization. We will test this hypothesis by monitoring and modulating the Wnt pathway during chick lens re-polarization. Combined, these studies will provide an in- depth assessment of the role of the Wnt pathway in lens development and overall, an important step forward in our understanding of this unique organ. In this application, we propose the study a cell-cell signaling pathway, the so-called Wnt pathway that is known to be critical for embryonic development, for tissue homeostasis and for the development of tumors. We will determine whether the Wnt pathway is responsible for determining the orientation of the lens within the eye and thus, whether this pathway is important for the unique optical capability of this organ
Keywords: Alleles; Allelomorphs; Anterior; Autoregulation; balance; balance function; biological signal transduction; Biology; Body Tissues; Cell Communication and Signaling; Cell Signaling; Cell to Cell Communication and Signaling; Cell-Cell Signaling; Cells; Complex; Coupled; Data; Development; Disease; disease/disorder; Disorder; Dysfunction; Embryo Development; Embryogenesis; Embryonic Development; Epithelial; Epithelial Cells; Epithelium; Equilibrium; experiment; experimental research; experimental study; Eye; Eyeball; failure; Failure (biologic function); Family; Family member; Feedback; fiber cell; FLR; Functional disorder; Genetic; Goals; high risk; Homeostasis; innovate; innovation; innovative; intercellular communication; Intracellular Communication and Signaling; lens; Lens Fiber; Ligands; loss of function; Mammals, Mice; Mice; minimal risk; Modeling; Monitor; Murine; Mus; Mutate; Names; Optics; Organ; pathophysiology; pathway; Pathway interactions; Pattern; Phosphorylation; Physiological Homeostasis; Physiopathology; prevent; preventing; Problem Solving; Production; progenitor; Protein Phosphorylation; public health relevance; receptor; Receptor Protein; recombinase; Regulation; research study; response; Retina; Role; Signal Pathway; Signal Transduction; Signal Transduction Systems; Signaling; social role; Source; T cell factor 3; Tcf3 transcription factor; Testing; Tissues; tool; transcription factor; tumor; Work
Relevance: In this application, we propose the study a cell-cell signaling pathway, the so-called Wnt pathway, that is known to be critical for embryonic development, for tissue homeostasis and for the development of tumors. We will determine whether the Wnt pathway is responsible for determining the orientation of the lens within the eye and thus, whether this pathway is important for the unique optical capability of this organ
Project start date: 2004-12-01
Project end date: 2015-02-28
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
PFA/PA: PA-10-067
2R01EY016241-06 (2011): $382084
AORTIC STIFFNESS AND HYPERTENSION IN OBESE MICE
A Richard, Professor Of Medicine
Boston University Medical Campuscity: Boston country: United States (us)
Grant 5R01HL105287-02 from National Heart, Lung, And Blood Institute
Abstract: With advancing age or prematurely in obese children, arterial stiffness increases and has been implicated in the development of hypertension. Because the aortic stiffness transmits higher pressure to the peripheral vasculature, it may also be causally related to the clinical complications of hypertension. Our preliminary studies in normal mice made obese by feeding a diet which is high in fat (30%) and sucrose (30%, HFHS), and is typical of that consumed by many Americans, show an association between increased aortic tone and stiffness present after 2-4 months of diet with systolic hypertension that is present after 10 months, but not after 2 months. At the earlier time point HFHS diet also impairs endothelium-dependent relaxation and increases oxidation of functionally significant aortic smooth muscle cell (SMC) proteins, including the sarcoplasmic reticulum Ca2+ ATPase (SERCA). As SERCA regulates the SMC response to nitric oxide (7NO), this suggests the hypothesis that abnormalities in SMC metabolism and oxidants caused by HFHS diet may impair 7NO function and lead to increased aortic tone and stiffness that may be causally related to the later development of hypertension. Our preliminary studies also show that polyphenols which activate the master metabolic regulator, sirtuin-1 (Sirt1), relax SMC and when added to HFHS diet, prevent both the early abnormalities in aortic tone and oxidants, as well as the late hypertension. This is consistent with the further hypothesis that HFHS diet-induced vascular metabolic abnormalities, oxidants, and stiffness are regulated by Sirt1 in SMC. The 3 aims will 1) test if there is a temporal and potentially causal relationship between the early 7NO dysfunction, increased oxidants, and stiffness of aortic SMC with the later development of systolic hypertension associated with obesity induced by HFHS diet in C57BL6 mice, 2) determine if a Sirt1-activating polyphenol or dietary fat reduction can reverse early metabolic mediators of aortic stiffness and prevent later hypertension, and 3) using transgenic mice with tissue-specific deletion of SMC Sirt1, test if SMC Sirt1 is a potential therapeutic target for improving aortic stiffness and hypertension caused by obesity. Obesity increases the complications of cardiovascular disease, including aortic stiffness and hypertension. Our studies will determine how oxidants arising from tissue metabolism in obese mice increase aortic stiffness and cause hypertension. As aortic stiffness precedes hypertension, we will test if ameliorating aortic oxidants and stiffness at a younger age can prevent the later development of hypertension
Keywords: Address; Age; American; angiogenesis; arterial stiffness; Atherosclerosis; Blood Pressure; Blood Vessels; Boston; Ca(2+)-Transporting ATPase; Caloric Restriction; Cardiovascular Diseases; Cardiovascular system; Child; Clinical; Development; Diet; Dietary Fats; Elderly; Endothelial Cells; Endothelium; Environment; experience; Fatty acid glycerol esters; feeding; Functional disorder; Funding; Hindlimb; Hypertension; improved; In Vitro; in vivo; Institutes; Lead; Measurement; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Molecular; Mus; Nitric Oxide; Obese Mice; Obesity; Oxidants; oxidation; Peripheral; Physiologic pulse; polyphenol; premature; pressure; prevent; programs; Proteins; public health relevance; Relaxation; Research; Research Personnel; response; Role; Sarcoplasmic Reticulum; Smooth muscle (tissue); Smooth Muscle Myocytes; Sucrose; systolic hypertension; Testing; therapeutic target; Time; Tissues; Transgenic Mice; Ultrasonography; United States National Institutes of Health; Universities
Relevance: Obesity increases the complications of cardiovascular disease, including aortic stiffness and hypertension. Our studies will determine how oxidants arising from tissue metabolism in obese mice increase aortic stiffness and cause hypertension. As aortic stiffness precedes hypertension, we will test if ameliorating aortic oxidants and stiffness at a younger age can prevent the later development of hypertension
Project start date: 2010-09-30
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: RFA-HL-10-027
5R01HL105287-02 (2011): $408834
TRANSCRIPTIONAL ELONGATION AND SPLICING IN HUMAN GENES IN SITU
A Richard, Staff
Cleveland Clinic Lerner Col/med-cwrucity: Cleveland country: United States (us)
Grant 5R01GM093074-02 from National Institute Of General Medical Sciences
Abstract: While the average human gene is on the order of 10-20 kb in length, the human genome also contains a significant number of genes which are much longer. Some genes can exceed one million base pairs in length. Many of these long genes also contain introns of hundreds of kilobases in length. These features represent an extreme challenge to the processes of transcription and RNA splicing. For RNA splicing, very large introns present the problem of identifying the correct splice sites and exons in spite of a background of similar "decoy" sequences present within the introns. The current models of splicing signals cannot properly predict the splicing pattern of large genes. To begin to address some of these problems, we have recently developed methods to measure the rate of RNA polymerase II (RNAPII) elongation and RNA splicing in large human genes in their in situ chromosomal locations and normal chromatin environments. We have shown that transcription proceeds rapidly in large genes and that splicing occurs co-transcriptionally within minutes of synthesis regardless of the length of the intron. We now have evidence that large introns are spliced in a single event implying that mechanisms must exist to suppress the use of decoy splice sites. We propose to use a variation of our previous experiment to investigate the temporal order of splicing factor binding to long introns in order to test current theories of exon definition. In addition to the splicing signals contained in the pre-mRNA, it is possible that splicing information could also be encoded in the structure of chromatin along genes. To support this idea, we have shown that exons are enriched in nucleosomes relative to adjacent intron sequences and that these exonic nucleosomes are also enriched in specific histone methyl marks. We propose to determine the function of these methyl marks by selectively removing or enhancing them by knocking down or over-expressing the specific methyltransferases. We will confirm these alterations by ChIP analysis and then we will measure the rate and fidelity of RNA splicing. Changes in alternative splicing will be detected by transcriptome analysis. Many accessory factors for RNAPII transcription elongation have been identified in in vitro and in vivo studies. However, few if any of these have been shown to be required for elongation of RNAPII in vivo in mammalian cells. Large genes in particular should be dependent on optimum elongation of RNAPII thus making these genes potentially useful for the analysis of these factors. We propose to examine these rates following modification of the gene expression machinery. First, we will use RNAi knockdowns of elongation factors to determine their in vivo roles in the transcription of long genes. We will also use mutant versions of RNAPII containing truncations and modifications of the important C-terminal domain to address the roles of this domain in transcription and splicing in large genes. These studies will advance our understanding of human gene expression which is of major relevance to both normal and pathological cell growth and development. The regulated expression of genes is central to human growth, development, normal and pathological functioning and the response of the body to changes in the internal and external environment. This proposal is designed to understand how in their natural chromosomal environment are correctly expressed in human cells. In particular, we propose experiments that probe expression mechanisms in genes that are substantially larger than average. Such large genes include several tumor suppressor genes which are inactivated in many human cancers. We hope to learn the rules and identify the factors that play roles in the expression of large genes in order to understand, predict and perhaps prevent the aberrrant expression of genes in pathological conditions
Keywords: Address; Affect; Alternative Splicing; base; Base Pairing; Binding (Molecular Function); C-terminal; cell growth; Cells; Chromatin; Chromatin Structure; coping; Data; demethylation; design; Elongation Factor; Environment; Event; Exons; Factor Analysis; Feedback; follow-up; gene conservation; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; genome-wide; Growth and Development function; histone modification; Histones; Human; Human Genome; In Situ; In Vitro; in vivo; insight; interest; Introns; Invertebrates; ITPR1 gene; Kinetics; knock-down; Knowledge; Learning; Length; Location; Malignant Neoplasms; Mammalian Cell; Measures; Methods; Methylation; Methyltransferase; Modeling; Modification; Molecular; Monitor; mRNA Precursor; mutant; Nature; Nucleosomes; Nucleotides; Pattern; Phylogeny; Play; prevent; Process; public health relevance; Publishing; Reaction; Relative (related person); research study; response; RNA; RNA Interference; RNA Polymerase II; RNA Splicing; Role; Signal Transduction; Site; Spliced Genes; Structure; System; Techniques; Testing; theories; To specify; Transcription Elongation; Transcription Process; Transfection; Tumor Suppressor Genes; Ursidae Family; Variant; Work
Relevance: The regulated expression of genes is central to human growth, development, normal and pathological functioning and the response of the body to changes in the internal and external environment. This proposal is designed to understand how in their natural chromosomal environment are correctly expressed in human cells. In particular, we propose experiments that probe expression mechanisms in genes that are substantially larger than average. Such large genes include several tumor suppressor genes which are inactivated in many human cancers. We hope to learn the rules and identify the factors that play roles in the expression of large genes in order to understand, predict and perhaps prevent the aberrrant expression of genes in pathological conditions
Project start date: 2010-09-24
Project end date: 2014-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-10-067
5R01GM093074-02 (2011): $295317
EPIGENOMIC CHANGES IN NORMAL T-CELL DEVELOPMENT AND LEUKEMOGENESIS
A Richard
Dana-farber Cancer Institutecity: Boston country: United States (us)
Abstract: While significant study has been directed at understanding the genetic basis of cancer, there is growing vidence that epigenetic mechanisms also play a significant role. Epigenetic mechanisms, such as hromatin modifications and DNA methylation, are stable, long-term (typically heritable) changes in the ranscriptional potential of a cell that are independent of changes in the underlying genomic sequence. These epigenetic modifications can reveal the transcriptional history and key control mechanisms for protein-coding and miRNA genes. T-cell acute lymphoblastic leukemia (T-ALL) is a neoplastic disorder of lymphoblasts arising in the T-cell lineage. The major subtype of human T-ALL can be defined by cytogenetic abnormalities and differentiation arrest at different stages of T-cell development. NOTCH1 serves as a unifying target in this model, as activating NOTCHI mutations have now been found in all of the most common subtypes of T-ALL and in more than 50% of all pediatric T-ALL cases. Our central hypothesis is that comparing the genome-wide epigenetic signatures of T-ALL cells to normal T cell precursors will lead to substantial new insights, including the identification of genes that are differentially regulated, as well as putative markers that might lead to early diagnosis and/or improved monitoring of the progress of tumor therapies. We propose to determine the dynamic changes to cell potential using high-quality epigenetic signatures of chromatin modifications and transcriptional potential during mammalian T cell development and leukemogenesis using a NOTCH-induced mouse model (AIM 1) to determine the epigenetic mechanisms involved in progression of the T-cell leukemias. Information gathered using the mouse models will complement epigenetic state of specific subtypes of human T-ALL with defined genetic mutations (TAL1 pos, +/- NOTCH mutations) (AIM 2). The long-range goal of this proposal is to identify the transcriptional history and key epigenetic control mechanisms genome-wide for all protein-coding and miRNA genes during mammalian T cell development and T cell leukemogenesis and thus provide a critical signature of leukemic identity
Keywords: Aberrant DNA Methylation; Accounting; Acute T Cell Leukemia; base; Binding (Molecular Function); biomarker; bisulfite; Cell Cycle Regulation; Cell Line; Cell Lineage; cell type; Cells; Childhood Precursor T Lymphoblastic Leukemia; Chromatin; chromatin modification; Chromosome abnormality; Clinical; Code; Complement; Development; Disease; DNA; DNA Methylation; DNA-Directed RNA Polymerase; Early Diagnosis; Epigenetic Process; epigenomics; Functional RNA; Gene Mutation; Gene Proteins; Genes; Genetic; Genetic Transcription; Genome; genome-wide; Genomics; Goals; histone modification; Histones; Human; Human Cell Line; improved; information gathering; insight; Lead; Lesion; leukemia; Leukemia, Lymphocytic, Acute; leukemia/lymphoma; Leukemic Cell; leukemogenesis; Link; lymphoblast; Malignant Neoplasms; Methylation; MicroRNAs; Modeling; Modification; Molecular; Monitor; mouse model; Mus; Mutation; neoplastic; notch protein; NOTCH1 gene; Oncogenic; Pathogenesis; Pathway interactions; Patients; Play; Precipitation; progenitor; Proteins; Recording of previous events; research study; Role; Site; Sorting - Cell Movement; Staging; T cell differentiation; T-Cell Development; T-Cell Leukemia; T-Lymphocyte; TAL1 gene; Technology; Thymus Gland; transcription factor; tumor
Relevance: T-Acute lymphoblastic leukemia (T-ALL) is characterized by a block in differentiation of T-cell progenitors, and an accumulation of immature lymphoblasts. Together with genetic changes, epigenetic alterations such as aberrant DNA methylation play a role in the molecular pathogenesis of the disease. Identifying the epigenetic mechanisms dysregulated in T-ALLmay lead to new epigenetic biomarkers and therapies
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5P01CA109901-07_7138 (2011): $426366
2P01CA109901-06_7138 (2010): $413948
2011 ELASTIN AND ELASTIC FIBERS GRS GRC
A Richard, Research Associate Professor Of Med
Gordon Research Conferencescity: West Kingston country: United States (us)
Grant 1R13HL110716-01 from National Heart, Lung, And Blood Institute
Abstract: We propose to organize and support the 2011 Gordon Research Conference and Gordon Research Seminar on Elastin and Elastic Fibers to be held July 23-29, 2011 at the University of New England in Biddeford, Maine. This is the leading international research conference on elastin and elastic fibers, which are critical components of the vasculature, lung, skin and other elastic tissues. The conference will open with the latest findings on the protein structure of elastic fiber components including fibrilins, fibulins, LTBPs and tropoelastin monomers and their assembly in vitro and in vivo. Building on this structural basis, we will next learn the latest findings about unexpected roles of elastic fiber components in controlling the bioavailability and activation of growth factors critical for development, tissue homeostasis, wound healing, and tissue regeneration. Next, leading investigators will present the latest findings in human genetic diseases of elastic fiber components and how these offer insights into protein function and assembly. Sessions on acquired human diseases of elastic fibers follow, spanning the vasculature, lung, and skin, and offering new insights into the roles of elastin-producing stem cell populations critical for tissue homeostasis and repair. These translationally-oriented sessions focus on the roles of elastic fiber components in the pathogenesis of diseases including bronchopulmonary dysplasia, COPD, systemic and pulmonary hypertension, aneurysms, and acquired skin disorders including UV damage-induced loss of dermal elasticity and dermal calcification. The conference culminates in sessions on the development of elastin- based biomaterials, their structural and biophysical properties, and their applications to regenerative medicine. The specific objectives and anticipated impact of the combined GRS/GRC conference in 2011 are 1) To gather diverse (gender, nationality, career stage and working environment) investigators from multiple disciplines together for a focused, comprehensive conference presenting the latest findings and ideas in elastin and elastic fiber research. 2) To foster collaborative opportunities between investigators which will inspire and facilitate multidisciplinary, systems biology and translational approaches to investigating protein structure and fibrillar assembly, the pathogenesis of acquired and genetic elastic fiber diseases in the vasculature, lung and skin, and progress in the development of elastin-based biomaterials and their application to regenerative medicine. 3) To encourage and mentor new trainees through the new Gordon Research Seminar toward career success in elastic fiber-related research and support them through travel and excellence awards
Keywords: Affect; Aging; American; Aneurysm; Atherosclerosis; Award; base; Biocompatible Materials; Biological Availability; Blood Vessels; Bronchopulmonary Dysplasia; calcification; career; Chronic Obstructive Airway Disease; Cutis Laxa; Deposition; Dermal; Development; Discipline; Disease; Elastic Fiber; Elastic Tissue; Elasticity; Elastin; Elastin Fiber; fibulin; Fostering; Gender; Genetic; Growth Factor; Health; Health Care Costs; Hereditary Disease; Homeostasis; human disease; Human Genetics; Hypertension; In Vitro; in vivo; Inherited; insight; interdisciplinary approach; International; Learning; Lung; Lung diseases; Maine; Marfan Syndrome; Mentors; monomer; multidisciplinary; Musculoskeletal Diseases; National Heart, Lung, and Blood Institute; Nationalities; New England; Pathogenesis; programs; Property; protein function; protein structure; Pulmonary Hypertension; Regenerative Medicine; repaired; Research; Research Personnel; Research Support; Role; Scientist; Skin; skin disorder; Staging; stem cell population; stroke; success; symposium; Systems Biology; tissue regeneration; Tissues; translational approach; Travel; Tropoelastin; ultraviolet damage; Universities; UV Radiation Exposure; Vascular Diseases; Vascular remodeling; Workplace; Wound Healing
Relevance: The 2011 Gordon Research Conference and Gordon Research Seminar on Elastin and Elastic Fibers will explore the latest research in elastic tissues and their diseases. Common diseases involving elastic fibers are chronic obstructive pulmonary disease (COPD), hypertension, aneurysms, stroke, atherosclerosis, UV damage to the skin, inherited skin disorders including cutis laxa, inherited musculoskeletal disorders such as Marfan´s syndrome, and loss of normal elasticity in tissues with aging and UV exposure. The conference attracts scientists from different disciplines and provides unique opportunities to develop integrative approaches to important questions about normal and impaired elastic fiber assembly, and the genetic basis for dominant, recessive and polygenic disorders involving elastic fiber tissues. The program has a strong translational focus with sessions highlighting the latest findings and strategies for defining the pathogenesis of acquired vascular, lung and skin diseases and new prospects for regenerative medicine
Project start date: 2011-07-01
Project end date: 2012-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-10-071
1R13HL110716-01 (2011): $34101
HIGHLY DIVERSE AND STRUCTURALLY VARIED HETEROCYCLIC LIBRARIES FOR THE MLSMR
A Richard, President
Torrey Pines Inst For Molecular Studiescity: Port St. Lucie country: United States (us)
Grant 5P41GM081261-03 from Roadmap Initiative, Office Of The Director
Abstract: We plan to use our expertise in the diversity oriented synthesis of small molecule compounds for the preparation of 18-22 structurally unique pharmacophores. Many of the proposed strategies and synthetic approaches have already been optimized and published, thus increasing the probability of success. The proposed pharmacophores will be generated using solid and solution phase methods. The synthetic approaches to be pursued, while direct and productive, are highly practical and reproducible. The proposed compounds will significantly enhance the MLSMR collection. We will use different strategies for the diversity-oriented synthesis of a variety of unique heterocyclic compounds. Solid phase synthesis will be used to generate triazinediones, guanidino-ureas, aminotetrazoles, indolines, aminotriazoles, azoniaspiro, oxopiperazinium, and bis-cyclic compounds. We will use solution phase chemistry to produce novel indole, piperidine, tetrahydroquinoline, and steroid libraries. Additionally, we will develop synthetic approaches for the synthesis of unique organofluorinated compounds including DD-difluorocarbonyl compounds and varied difluoro-tetrahydropyrimidine derivatives. Fluorine-containing compounds have played a special role in medicinal chemistry and biomedical applications due to the unique influence of fluorine atoms on biological activity. In keeping with the themes of the investigator´s research, we will target libraries of "Favored Pharmacophores" and employ the "Heteroatom Incorporation Strategy (HIS)" to generate novel libraries using diversity-oriented synthesis. The libraries are designed in a manner to balance size, diversity and complexity, and to optimize purity. This is essential to avoid false positives during the screening process. All proposed small molecule libraries are designed to follow known drug-likeness rules including ´Lipinski´s Rule of Five´. All structurally unique libraries will consist of 100-200 individual compounds (10 to 20 mg of each) and will be prepared with purity equal or higher than 90% as required by the RFA. These will be transferred to the repository with detailed experimental protocols and solubility information. The libraries proposed were selected in a manner which does not overlap in chemical space with molecules currently in the PubChem database. The majority of the chemistries are well established in the Pi´s and Co-Pi´s laboratories. There has been and continues to be, a longstanding collaborative interaction between the Pis at Torrey Pines Institute for Molecular Studies and the Burnham Institute for Medical Research, which is part of the Molecular Library Screening Center Network (MLSCN). We thus have ready access to equipment and personnel at both organizations and to the MLSCN
Keywords: 1H-1, 2, 4-Triazol-3-amine; 2, 3-dihydro-1H-indole; 3-Amino-1, 2, 4-triazole; Aminotriazole; Amitrole; balance; balance function; base; Biological; Carbamide; Chemicals; Chemistry; Chemistry, Pharmaceutical; clinical data repository; clinical data warehouse; Collection; cyclic compound; Data Banks; Data Bases; data repository; Databank, Electronic; Databanks; Database, Electronic; Databases; design; designing; diketopiperazine; drug/agent; Drugs; Elaqua XX; Equilibrium; Equipment; F element; Fluorine; Goals; Guanidines; Heterocyclic Compounds; Human Resources; Imines; Individual; Indoles; indoline; Institutes; Investigators; Laboratories; Libraries; Manpower; Medical Research; Medication; Medicinal Chemistry; Method LOINC Axis 6; Methodology; Methods; Molecular; Molecular Bank; National Institutes of Health; National Institutes of Health (U.S.); NIH; novel; personnel; Pharmaceutic Chemistry; Pharmaceutic Preparations; Pharmaceutical Chemistry; Pharmaceutical Preparations; pharmacophore; Phase; Piperazines; piperidine; Play; Preparation; Probability; Process; Property; Property, LOINC Axis 2; Protocol; Protocols documentation; Publishing; relational database; repository; Research; Research Personnel; Researchers; Role; S Period; S Phase; S phase (cell cycle); Science of Chemistry; screening; Screening procedure; screenings; small molecule; small molecule libraries; social role; Solid; solid solution; Solubility; Solutions; Steroid Compound; Steroids; success; Synthesis Period; Synthesis Phase; United States National Institutes of Health; Urea; Urea Carbamide; Ureaphil
Project start date: 2007-09-05
Project end date: 2011-08-31
Budget start date: 1-SEP-2009
Budget end date: 31-AUG-2011
PFA/PA: RFA-RM-06-003
5P41GM081261-03 (2009): $459036
MOLECULAR MECHANISMS OF INTESTINAL ATROPHY/HYPERPLASIA
A Richard, Professor
Massachusetts General Hospitalcity: Boston country: United States (us)
Grant 5R01DK047186-15 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: We have identified an important adaptive response that occurs in the mammalian gut in the setting of starvation and disease, silencing of the enterocyte differentiation marker gene, intestinal alkaline phosphatase (IAP). Based upon its functions in regard to dietary fat absorption and cellular resistance to toxins (such as LPS) and microbes, the silencing of IAP expression likely has important physiological consequences for the host. As such, the broad aims of this proposal are to delineate the mechanisms that govern IAP gene regulation. Ultimately, we hope to identify therapeutic targets that could be used in the clinical setting to treat patients in the context of starvation and other gut-related conditions. The three specific aims of this proposal represent complementary and distinct approaches to understanding enterocyte differentiation in both normal and pathologic conditions. Aim#1 is based upon our observation that ectopically expressed IAP leads to a remarkable change in enterocyte phenotype, characterized by resistance to LPS and Salmonella. Accordingly, we will examine three transcription factor pathways that activate IAP expression (KLF4, Cdx1, and ZBP-89). Each of these factors will be expressed within intestinal epithelial cells in vitro in order to determine whether they result in altered host cell function in regard to LPS and Salmonella. In Aim #2 we will dissect a single transcriptional pathway using a well-established inducible cell culture system. Chromatin Immuno-precipitation (ChIP) will be used to define the precise changes in chromatin structure that occur when an individual transcription factor (KLF4) binds and activates a specific target gene (IAP). We will examine the secondary modifications that occur in the histone proteins in response to KLF4 binding, the role of associated proteins, and also determine those changes that occur as the IAP gene is turned off. In Aim #3 we will focus on the enterocyte adaptation that occurs in response to diseases and stress. We will use both in vitro and in vivo model systems to examine the molecular mechanisms that govern IAP gene repression in the contexts of starvation and inflammation. Taken together, these studies will have important implications for our understanding of normal intestinal physiology, as well as the gut response to disease states
Keywords: Absorption; absorption; Acetylation; Affect; Alkaline Phosphatase; alkaline phosphomonoesterase; Antibodies; Antigens, Differentiation; Assay; Atrophic; Atrophy; Award; base; Binding; Binding (Molecular Function); Bioassay; Biologic Assays; Biological Assay; Biological Models; Blood Serum; bloodstream infection; bowel; Cell Culture System; Cell Culture Techniques; Cell Function; Cell physiology; Cell Process; Cells; Cellular Function; Cellular Physiology; Cellular Process; ChIP (chromatin immunoprecipitation); CHIP assay; Chromatin; chromatin immunoprecipitation; Chromatin Structure; Clinical; cytokine; deprivation; Dietary Fats; dietary lipid; Differentiation Antigens; Differentiation Markers; Disease; disease/disorder; Disorder; DISSEC; Dissection; Dysfunction; Enterocytes; Epithelial; Epithelial Cells; failure; Failure (biologic function); FLR; Functional disorder; Funding; gastrointestinal epithelium; Gene Action Regulation; Gene Activation; Gene Down-Regulation; Gene Expression; Gene Expression Regulation; Gene Inactivation; gene product; Gene Regulation; Gene Regulation Process; gene repression; Gene Silencing; Gene Targeting; Gene Transcription; Genes; genetic regulatory element; genetic regulatory protein; Genetic Transcription; glycerophosphatase; Gut Epithelium; heavy metal lead; heavy metal Pb; Histone Code; Histones; Hyperplasia; Hyperplastic; In Vitro; in vitro Model; in vivo; in vivo Model; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Bowel Disorder; Inflammatory Intestinal Disease; Inflammatory Intestinal Disorder; INFLM; Intestinal; Intestines; Investigators; Lead; Lipopolysaccharides; LPS; Marker Antigens; Markers, Differentation; Methylation; Microbe; Model System; Models, Biologic; Modification; Molecular; Molecular Interaction; Morbidity; Morbidity - disease rate; Mortality; Mortality Vital Statistics; Nucleic Acid Regulatory Sequences; Orthophosphoric-monoester phosphohydrolase (alkaline optimum); Pathologic; pathophysiology; pathway; Pathway interactions; Patients; Pb element; Phenotype; Physiologic; Physiological; Physiology; Physiopathology; Play; Precipitation; Process; Process of absorption; programs; Programs (PT); Programs [Publication Type]; Protein Methylation; Proteins; Regulator Regions, Nucleic Acid; regulatory gene product; Regulatory Protein; Regulatory Regions; Regulatory Regions, Nucleic Acid (Genetics); Regulatory Sequences, Nucleic Acid; Research Design; Research Personnel; Research Proposals; Researchers; Resistance; resistant; response; RNA Expression; Role; Salmonella; Sepsis; Serum; social role; Starvation; Stress; study design; Study Type; Subcellular Process; Targetings, Gene; therapeutic target; Toxin; Transcription; Transcription Activation; transcription factor; Transcription Repression; Transcription, Genetic; Transcriptional Activation; Transcriptional Repression; Trauma; Up-Regulation; Work
Project start date: 1994-08-01
Project end date: 2011-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
5R01DK047186-15 (2011): $310461
NEW EVIDENCE ON THE PERSISTENCE OF HIGH HEALTH SPENDING
A Richard, Professor
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Abstract: To the extent that high health care spending persists over time, problems of adverse selection would be accentuated in private insurance markets based on annual contracts, exacerbating concerns about the availability of affordable coverage. Despite the importance of understanding the persistence of medical spending, surprisingly little is known. Several studies are based on Medicare data, limiting generalizability to the under 65 population. Studies representing younger persons have limitations, including the lack of recent data, short follow-up, single employer or insurer samples, and lack of attention to attrition from employer-based coverage. New knowledge regarding spending persistence can improve the evidence base underlying many policy options for covering the uninsured, including subsidized reinsurance markets, Medicare buy-ins, and incentives to expand the role of individual insurance contracts and consumer-driven health plans. We will assess the persistence of health care costs using the 2002-2007 Thomson Healthcare MarketScan Database, which includes claims data for individuals insured through over 100 large firms, and the 2001-2006 waves of the MEPS. Spending categories will be based on cut points in the annual spending distribution (e.g., top 5%). The primary analyses will focus on individuals under age 65. Subanalyses will be done by age/gender group and for selected clinical conditions and Medicare-eligible retirees. Predictors of cost patterns will include demographics, health plan design, and comorbid conditions. Because the MEPS has a limited sample size and follows households for only two years, the primary analyses will use MarketScan data to provide a longer panel on a large sample. Over 3 million people can be followed for at least 5 years. The MEPS will be used to assess the generalizability of the MarketScan findings and the effects of attrition from employer coverage on estimates of spending persistence based on private insurer claims. The analytic approach is to characterize the run-up to high spending periods and the persistence of high spending over time by 1) describing the cost distribution, transition probabilities, and spending correlations across categories over time (e.g., from top 50% to top 5%), and 2) modeling the predictors of transitioning between distributional categories as a function of employee and household characteristics, and the predictors of attrition from the MarketScan database. The resulting estimates can inform policy simulations addressing issues such as the cost of reinsurance under different stop-loss thresholds, and the potential magnitude of adverse selection in expanded individual insurance markets or Medicare buy-ins. We will provide an example of how such estimates can inform the evaluation of risk-adjustment and reinsurance as mechanisms to improve the functioning of small group health insurance markets
Relevance: New knowledge regarding persistence of health spending can improve the evidence base underlying most of the policy options for covering more of the uninsured, including subsidized reinsurance markets, Medicare buy-ins, and incentives to expand the role of individual insurance contracts. To provide such evidence, we will assess the persistence of health care costs using the 2002-2007 Thomson Reuters MarketScan Database, which includes claims data for individuals insured through about 100 large firms, and the 2001-2006 waves of the MEPS. 1
Project start date: 2009-07-01
Project end date: 2011-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2011
PFA/PA: PA-07-243
1R01HS017706-01A1 (2009): $0
ROLE OF GTP-BINDING/TRANSGLUTAMINASE IN CELL SURVIVAL AND MIGRATION
A Richard, Professor
Cornell University Ithacacity: Ithaca country: United States (us)
Grant 5R01GM061762-12 from National Institute Of General Medical Sciences
Abstract: Tissue transglutaminase-2 (TGase-2) has been suggested to be involved in a number of vitally important biological responses ranging from neuronal differentiation and neurodegenerative diseases to the regulation of cell growth and various cancer-associated activities including extracellular matrix modulation and metastasis. However, thus far, relatively little is known regarding the molecular basis by which TGase-2 participates in this broad array of cellular and biological processes. What makes this protein especially interesting is that it is capable of GTP-binding and hydrolytic activities like signaling G-proteins, as well as an enzymatic cross-linking (transamidation) activity that catalyzes the covalent linkages between glutamine residues and primary amino groups, resulting in the formation of new protein-protein and protein-polyamine complexes. During the past funding period, we have found that these different functions enable TGase-2 to play an essential part in ensuring the survival of various cells against apoptotic challenges, as well as having a key role in the EGF-stimulated anchorage-independent growth, migration, and invasive activity of cancer cells. In this renewal application, we propose to build on these different findings to learn more about the EGF-dependent signaling pathways that regulate TGase-2 expression and function, as well as the mechanisms by which TGase-2 contributes to EGF-stimulated cell growth and migration. This will entail the following lines of investigation. 1) Understanding the role of TGase-2 in the anchorage-independent growth of breast cancer cells. Here we will set out to determine how EGF stimulates the up-regulation of TGase-2 in breast cancer cell lines and how this enhances their ability to grow in the absence of a substratum. 2) Understanding the role of TGase-2 in cell migration. These studies will identify the signals used by EGF to direct the recruitment of TGase-2 to the plasma membrane surface and the leading edges of cells, and determine why TGase-2 is necessary for EGF- stimulated cell migration. 3) Understanding how TGase-2 is secreted from cells and why this provides protection against apoptotic challenges. This line of study stems from our findings that secreted/extracellular TGase-2 plays an important role in protecting cells against apoptosis-inducing stimuli. We will determine the mechanism by which TGase-2 is secreted from cells, how this provides a survival advantage, and whether this also accounts for the role played by TGase-2 in EGF-stimulated invasive activity. By understanding the mechanisms of action and regulation of TGase-2, we expect to gain new insights into fundamentally important cellular signaling activities responsible for cell survival and growth factor-stimulated cell migration. These studies should also provide us with a better understanding of how the de-regulation of this interesting protein can contribute to various pathological conditions such as the development of metastatic cancers. PUBLIC HEALTH RELEVANCE Tissue transglutaminase is an interesting multi-functional protein that has been implicated in making cancer cells resistant to chemotherapeutic drugs as well as in promoting the metastatic potential of these cells. It also has been linked to neurodegenerative disorders, especially Alzheimer´s disease. Thus, by understanding how tissue transglutaminase is regulated and performs its normal functions in cells, and what events lead to its inappropriate actions, we hope to obtain information that will shed new light on the development of malignant cancers and possibly other disease states and degenerative disorders. The expectation is that this information will highlight novel targets and strategies for therapeutic intervention
Keywords: Accounting; Actins; Address; Agar; Alzheimer`s Disease; Amines; amino group; Anchorage-Independent Growth; Apoptosis; Apoptotic; base; Behavior; Biological; Biological Process; Brain; Breast Cancer Cell; cancer cell; Cancer cell line; Cell Death; cell growth; cell growth regulation; Cell Line; Cell membrane; cell motility; Cell physiology; Cell Survival; cell type; Cells; chemotherapeutic agent; Complex; Conditioned Culture Media; crosslink; Cues; Degenerative Disorder; deprivation; Development; Disease; Disseminated Malignant Neoplasm; EGF gene; Ensure; Epidermal Growth Factor Receptor; Epithelial Cells; Equilibrium; Event; Exhibits; expectation; extracellular; Extracellular Matrix; Fibroblasts; Funding; genetic regulatory protein; Glutamine; Goals; Growth; Growth Factor; GTP Binding; GTP-Binding Proteins; Guanosine Triphosphate; Health; Hela Cells; Human; In-Migration; inhibitor/antagonist; insight; interest; Investigation; Lead; Learning; Light; Link; link protein; Lysine; Malignant - descriptor; malignant breast neoplasm; Malignant neoplasm of cervix uteri; Malignant Neoplasms; malignant state; Mammary gland; MDA MB 231; migration; Molecular; monolayer; Neoplasm Metastasis; Neurodegenerative Disorders; Neuronal Differentiation; novel; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Polyamines; Proliferating; protective effect; Proteins; receptor coupling; Regulation; Resistance; response; rho GTP-Binding Proteins; RNA Splicing; Role; Serum; Signal Pathway; Signal Transduction; SKBR3; stem; Stimulus; Surface; Therapeutic Intervention; Tissues; trafficking; Transferase; transglutaminase 2; Transglutaminases; United States National Institutes of Health; Up-Regulation (Physiology); Variant; Work
Project start date: 2000-06-01
Project end date: 2012-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PA-07-070
5R01GM061762-12 (2011): $274208
Sponsored Links Excellgen http://Excellgen.com
THE ROLE OF BCL-RAMBO IN THYMIC INVOLUTION
A Richard
Yale Universitycity: New Haven country: United States (us)
Grant 5R01AI082030-03 from National Institute Of Allergy And Infectious Diseases
Abstract: Thymic involution is one the major changes that occur in the immune system with age (reviewed in (1)). The reduction of the size and function of the thymus lead to a decreased number of naive T cells in the periphery, compensated by homeostatic proliferation of peripheral memory T cells. As a consequence, the diversity of T cell antigen receptors and the immune responsiveness are reduced in aged individuals. Although the impact of aging on thymocytes, thymic progenitors and thymic microenvironment have been well characterized during the past few years, the genetic determinants and the molecular mechanisms responsible for thymic involution are still poorly understood. We recently discovered that Bcl-Rambo, a member of the Bcl-2 family of apoptotic regulators, is involved in the regulation of thymic involution. Notably, mice lacking this protein display a slower reduction of thymic size with age. The proposed project intends to characterize the role of Bcl-Rambo in the regulation of thymic involution. This study could lead to the identification of potential targets for pharmacological intervention to mitigate thymic involution and its physiological effects. Bcl-Rambo is one of the first proteins described to date, that positively regulates the process of age-related involution of the thymus. With this application we have the opportunity to assess the relative contributions of age-related deficiencies in lymphohematopoietic progenitor function; peripheral or intrathymic signals that regulate involution; and changes in the thymic microenvironment that contribute to the decline in na¿ve immune cell production, differentiation, and function
Keywords: Age; age dependent; age related; aged; Aging; Aging Process; Aging-Related Process; Apoptotic; biological signal transduction; body system, allergic/immunologic; Cell Communication and Signaling; Cell Function; Cell physiology; Cell Process; Cell Signaling; Cells; Cellular Function; Cellular Physiology; Cellular Process; Development; Family; gene product; genetic determinant; Genetic Determinism; heavy metal lead; heavy metal Pb; Immune; Immune system; Individual; Intervention; Intervention Strategies; interventional strategy; Intracellular Communication and Signaling; Lead; Lymphoid; Major Histocompatibility Complex Receptor; Mammals, Mice; member; memory T lymphocyte; MHC Receptor; Mice; Molecular; Murine; Mus; organ system, allergic/immunologic; Pb element; Peripheral; Physiologic; Physiological; Production; progenitor; Proteins; Receptors, Antigen, T-Cell; Regulation; Relative; Relative (related person); Reticuloendothelial System, Thymus; Role; Senescence; senescent; Signal Transduction; Signal Transduction Systems; Signaling; social role; Subcellular Process; T memory cell; T-Cell Receptor; T-Cells; T-Lymphocyte; thymocyte; Thymocyte Development; Thymus; thymus derived lymphocyte; Thymus Gland; Thymus Proper; Thymus-Dependent Lymphocytes
Relevance: Narrative Bcl-Rambo is one of the first proteins described to date, that positively regulates the process of age-related involution of the thymus. With this application we have the opportunity to assess the relative contributions of age-related deficiencies in lymphohematopoietic progenitor function; peripheral or intrathymic signals that regulate involution; and changes in the thymic microenvironment that contribute to the decline in na¿ve immune cell production, differentiation, and function
Project start date: 2009-02-17
Project end date: 2014-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: RFA-AI-08-012
5R01AI082030-03 (2011): $368651
IDENTIFICATION OF TARGET GENES FOR LHX3 IN GONADOTROPES
A Richard, Professor
Oregon Health And Science Universitycity: Portland country: United States (us)
Grant 1R21HD065529-01A1 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: This request for R21 funding seeks to use exploratory studies to understand the gene expression networks that regulate the development and function of the gonadotrope cells of the anterior pituitary. In particular, the studies seek to identify target genes that are regulated by the LIM homeodomain transcription factor, LHX3. Mutations in mice or humans that inactivate LHX3 have been found to drastically decrease production and secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH). Developmental studies have shown that loss of hormone secretion is due to loss of the appropriate, differentiated cells that produce LH and FSH. There is evidence that LHX3 plays a role in regulating the genes encoding the glycoprotein hormone -subunit, the FSH -subunit, and the gonadotropin releasing hormone receptor. Thus LHX3 plays an essential role in both the development of gonadotropes and the function of mature, differentiated gonadotropes. In view of the development role of LHX3, it seems likely that LHX3 binds to and regulates the activity of a number of important target genes in gonadotropes. The proposed studies seek to use newly developed massively parallel DNA sequencing to identify target genes regulated by LHX3 in gonadotropes. The specific aims include 1) Use chromatin immunoprecipitation and massively parallel, high throughput DNA sequencing to identify in vivo binding sites for LHX3 in the L T2 and T3-1 gonadotrope cell line. 2) Identify transcripts that are functionally regulated by LHX3 by identifying specific mRNAs that are decreased after shRNA knockdown of LHX3. Changes in mRNA populations will be assessed by massively parallel, high throughput sequencing of RNA. Comparing the list of genes with in vivo binding sites for LHX3 with the list of genes regulated by LHX3 should identify target genes that are functionally regulated by direct binding of LHX3. We believe that the results have the potential for high impact by providing new information about the gene regulatory network important for development and function of gonadotropes. The proposed studies should be relevant to the very important general issue of understanding how the information in the genome is used to specify all of the different cell types of the body. The findings should also have significance for the understanding of pituitary development and gene expression and increase understanding of how mutations lead to deficiencies in gonadotropin production and human disease
Keywords: Address; Adenohypophysis; Adenoviridae; Adenoviruses; Anterior Lobe of Pituitary; Anterior Lobe of the Pituitary Gland; Anterior pituitary; Anterior Pituitary Gland; Binding; Binding (Molecular Function); Binding Sites; Cell Body; cell body (neuron); Cell Line; Cell Lineage; Cell Lines, Strains; cell type; CellLine; Cells; Chemotherapy-Hormones/Steroids; ChIP (chromatin immunoprecipitation); CHIP assay; chromatin immunoprecipitation; combinatorial; Combining Site; Complex; cultured cell line; dam methylase; Dam methyltransferase; Development; DNA Sequence; Endocrine Gland Secretion; Follicle Stimulating Hormone; Follicle Stimulating Hormone-Releasing Hormone Receptors; Follitropin; Foundations; FSH; Funding; Future; Gene Components; Gene Expression; Gene Targeting; Genes; Genes, Regulator; Genetic; Genetic Alteration; Genetic Change; Genetic defect; Genome; genome mutation; genome wide association scan; genome wide association studies; genome wide association study; genome-wide; genome-wide scan; genomewide association scan; genomewide association studies; genomewide association study; genomewide scan; Genomics; Glycoproteins; Goals; Gonadotrope Cell; Gonadotropin-Releasing Hormone Receptor; Gonadotropins; GWAS; heavy metal lead; heavy metal Pb; Homeo Domain; homeodomain; Hormones; Human; human disease; Human, General; Hypophysis; Hypophysis Cerebri; in vivo; Individual; insight; Interstitial Cell Stimulating Hormone; Interstitial Cell-Stimulating Hormone; Lead; Leuteinizing Hormone; LHFSHRH Receptors; loss of function mutation; Luteinizing Hormone; Luteinizing Hormone Releasing-Hormone Receptor; Lutropin; Mammals, Mice; Man (Taxonomy); Man, Modern; Measures; Mediating; Messenger RNA; Mice; Molecular Interaction; mRNA; Murine; Mus; Mutation; Nature; Nervous System, Pituitary; neural cell body; neuronal cell body; new technology; Pars Anterior Pituitary Gland; Pb element; Pituitary; Pituitary Gland; pituitary gland development; Pituitary Gland, Anterior; Pituitary Lutenizing Hormone; Play; Population; Production; public health relevance; Reactive Site; Receptors, GnRH; Receptors, Gonadoliberin; Receptors, Gonadorelin; Receptors, LHRH; Receptors, Luliberin; Recombinant Luteinizing Hormone; Regulator Genes; regulatory gene; response; RNA Sequences; RNA, Messenger; Role; short hairpin RNA; shRNA; Site; small hairpin RNA; social role; soma; Specific qualifier value; Specified; Targetings, Gene; Testing; Therapeutic Hormone; Therapeutic LH; Tissue Differentiation; To specify; trans acting element; Transcript; transcription factor; Transcription Regulation; Transcriptional Control; Transcriptional Regulation; Transcriptional Regulatory Elements; whole genome association studies; whole genome association study
Relevance: The proposed studies should be relevant to the very important general issue of understanding how the information in the genome is used to specify all of the different cell types of the body. The findings should also have significance for the understanding of pituitary development and gene expression and increase understanding of how mutations lead to deficiencies in gonadotropin production and human disease
Project start date: 2011-01-01
Project end date: 2012-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-10-069
1R21HD065529-01A1 (2011): $231000
GRADUATE TRAINING IN MOLECULAR AND CELLULAR PHARMACOLOGY
A Richard, Kellet Professor
University Of Wisconsin Madisoncity: Madison country: United States (us)
Grant 3T32GM008688-12S1 from National Institute Of General Medical Sciences
Abstract: This renewal application requests continuing support for the Molecular and Cellular Pharmacology Predoctoral Training (MCP) Program at the University of Wisconsin-Madison. Graduate training in pharmacology has been strong at Wisconsin for many decades and is distributed among a number of departments and colleges. In 1994, the Pharmacology training faculty at Wisconsin joined together under the auspices of the Molecular and Cellular Pharmacology Program. This has created a campus-wide nucleus of faculty who are highly interactive scientifically and share an interest in training modern pharmacologists. The Molecular and Cellular Pharmacology Program has been strongly supported across campus. This initiative ahs revitalized the campus-wide Pharmacology curriculum, seminar series, and has sparked innumerable interdepartmental research and training activities that have enriched the environment for modern Pharmacology training. These changes have been very attractive to students with an interest in molecular and cellular pharmacology, and this has resulted in the recruiting and training of an outstanding cohort of young scientists to the Graduate Program. To fully take advantage of this superior training environment, this proposal is requesting continuing funds for the training of predoctoral students, starting with an increase of to 12 starting with year 10. The Program is designed to provide graduate students with interdisciplinary and integrated training in fundamental concepts in modern pharmacology with an emphasis on biochemical, molecular and cellular approaches with clear applications to human health. The didactic curriculum provides a solid base in all of these disciplines and is built on a strong foundation of rigorous in depth research training in modern pharmacology. Although the training emphasizes a research career, the training experience is designed to develop leadership and teaching abilities as well. All of the preceptors have peer-reviewed, active, and aggressive research programs that offer training opportunities in most areas of molecular and cellular pharmacology. With continued NIH support, the MCP Program will continue to enhance its tradition of providing the U.S. biomedical and pharmacological communities with expertly trained research scientists. These scientists are the future of biomedical research in Pharmacology
Keywords: Molecular; Pharmacology; Training
Project start date: 2009-09-01
Project end date: 2011-08-31
Budget start date: 1-SEP-2009
Budget end date: 31-AUG-2011
3T32GM008688-12S1 (2009): $87028
CVD AND METABOLIC COMPLICATIONS OF HIV/AIDS DATA COORDINATING CENTER
A Richard, Research Associate Professor
University Of Washingtoncity: Seattle country: United States (us)
Grant 5R01HL095126-04 from National Heart, Lung, And Blood Institute
Abstract: This proposal is written in response to an NHLBI FOA requesting a Data Coordinating Center (DCC) for RFA-HL-08-003 Mechanisms and Management of Cardiovascular and Metabolic Complications of HIV/AIDS. The purpose of the FOA is to foster collaborative research to elucidate the underlying mechanisms of metabolic and anthropometric abnormalities seen in HIV infection and highly active antiretroviral therapy and their relationship to cardiovascular disease risk. In this application, we propose to run the DCC from the Collaborative Health Studies Coordinating Center (CHSCC) at the University of Washington. The DCC will be responsible for coordinating studies at 6-7 clinical sites engaged in separate, but complimentary research agendas. Although the studies will all involve research that addresses the title of this RFA, the size and scope of these studies has yet to be fully determined. The DCC will play a key role in coordination and management of these studies. Its key responsibilities will include facilitation of data harmonization, standardization of study protocols where appropriate, facilitating data and specimen banking, scheduling and facilitating investigator meetings, coordinating centralized readings of cardiac evaluations and providing statistical expertise and support in protocol development, data analysis and preparation of presentations and manuscripts. This application describes our relevant experience and preparedness in these areas as well as others crucial to efficiently running a DCC. It also presents our plans for running the DCC for this group of studies. HIV-infected individuals have increased life expectancies since the introduction of highly active antiretroviral therapy (HAART). With this increased life expectancy come increased incidences of metabolic complications and cardiovascular disease (CVD) associated with living with HIV/AIDS and prolonged exposure to HAART. Studying how these diseases interact with HIV and HAART can help prevent their development and progression in HIV-infected individuals. (End of )
Keywords: ing; Address; AIDS/HIV problem; Area; biomarker; Calcium; Cardiac; Cardiovascular Diseases; cardiovascular disorder risk; cardiovascular risk factor; Cardiovascular system; Clinic Visits; clinical research site; Communication; Coronary; Coronary Arteriosclerosis; Data; Data Analyses; Data Collection; Data Coordinating Center; data integration; Databases; design; Development; Directories; Disease; disorder risk; Documentation; Ensure; Evaluation; experience; Exposure to; Fostering; Funding Opportunities; Goals; Health; Highly Active Antiretroviral Therapy; HIV; HIV Infections; imaging modality; Incidence; Individual; Life; Life Expectancy; Manuscripts; Medical; meetings; Metabolic; Methodology; National Heart, Lung, and Blood Institute; Nature; novel; Patients; Play; Preparation; prevent; programs; protocol development; Protocols documentation; Publications; Published Directory; Randomized; Readiness; Reading; Reporting; repository; Research; Research Activity; Research Design; Research Personnel; Resources; response; Running; Sample Size; Schedule; Scheme; Site; Specimen; Standardization; symposium; tool; treatment strategy; Universities; Washington; web site; Writing
Relevance: RELEVANCE HIV-infected individuals have increased life expectancies since the introduction of highly active antiretroviral therapy (HAART). With this increased life expectancy come increased incidences of metabolic complications and cardiovascular disease (CVD) associated with living with HIV/AIDS and prolonged exposure to HAART. Studying how these diseases interact with HIV and HAART can help prevent their development and progression in HIV-infected individuals
Project start date: 2008-09-25
Project end date: 2013-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: RFA-HL-08-003
5R01HL095126-04 (2011): $1002936
CHINA-CALIFORNIA ENVIRONMENTAL HEALTH TRAINING PROGRAM
A Richard
Sequoia Foundationcity: La Jolla country: United States (us)
Grant 5D43TW005741-10 from Fogarty International Center
Abstract: This proposal continues and expands the research and training program between the Shanghai Municipal Center for Disease Control (SCDC) and the California Department of Health Services (CDHS) Environmental Health Investigations Branch (EHIB), first established under FIC ITREOH sponsorship in 2002. The proposed training program is organized to foster development of environmental and occupational health research capacity and the translation of research into appropriate public policy. It is built around the three core components of our original program 1) California-based training for selected trainees, 2) China-based conferences to share experiences and information with an expanded network of Chinese environmental and occupational health colleagues, and 3) SCDC research capacity building activities that strengthen surveillance systems and research support facilities. The program expansion includes 1) increasing the number of trainees coming to California, 2) establishing Chinese-based workshops on laboratory methods and instrumentation, and 3) creating a grant program to fund applications from researchers affiliated with SCDC. We will also create a SCDC Resource Center to bring training and information to district CDCs and local health centers in Shanghai and provinces in southern China. Our training program is aligned with the goals of the sponsoring federal agencies. The training will be organized around modules that build on our experiences and that address the primary objectives of this Request for Applications, namely in-country infrastructure development, research implementation, information dissemination, mitigation of adverse consequences of environmental and occupational exposures, and evaluation of success. It is a unique government-to-government, applied training program that builds epidemiological and allied public health professional skills to implement complex studies that serve the public health needs of Shanghai inhabitants. The training is provided to mid-career researcher/managers who shoulder the responsibility for protecting the public health. Thus, this program is structured to translate environmental and occupational health research to action and policy and thereby be of direct and immediate benefit to Shanghai´s 17,000,000 people. The program is also able to leverage FIC funds with in-kind contributions of staff/resources from CDHS. As the California state health agency responsible for community intervention in response to environmental health events or concerns, EHIB is the agency best able to take the lead in providing training on research that emphasizes corresponding health interventions and public health policy. It also acts as a liaison to other CDHS programs. The collaboration, now in its 6th year, is well situated to address the leading municipal and regional environmental and occupational public health threats that now face a rapidly developing China
Keywords: Address; adverse outcome; Ally; base; California; career; CDC; Centers for Disease Control; Centers for Disease Control (U.S.); Centers for Disease Control and Prevention; Centers for Disease Control and Prevention (U.S.); China; Chinese; Chinese People; Collaborations; community intervention; Complex; conference; Country; Development; Development and Research; Educational workshop; Environmental and Occupational Exposure; Environmental Health; Environmental Health Science; Epidemiology; Evaluation; Event; experience; Face; facial; Fostering; Funding; Goals; Government; Grant; Health; health care policy; Health Care Professional; health care service; Health Policy; Health profession; Health Professional; Health Services; health training; Healthcare professional; Healthcare worker; heavy metal lead; heavy metal Pb; Information Dissemination; infrastructure development; instrumentation; Instrumentation, Other; Intervention; Intervention Strategies; interventional strategy; Investigation; Investigators; Laboratories; language translation; Lead; Mainland China; Methods; NIH RFA; Occupational; Occupational Health; Pb element; Policies; programs; Programs (PT); Programs [Publication Type]; PROV; Province; Public Health; public health medicine (field); Public Policy; R & D; R&D; Request for Applications; Research; research and development; Research Personnel; Research Resources; Research Support; Research Training; Researchers; Resources; response; Shoulder; skills; Structure; success; symposium; systems research; Training; Training Programs; Translating; Translatings; translation research enterprise; Translational Research; Translational Research Enterprise; Translational Science; United States Centers for Disease Control; United States Centers for Disease Control and Prevention; Workshop
Project start date: 2001-09-29
Project end date: 2012-02-29
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
PFA/PA: RFA-TW-06-004
5D43TW005741-10 (2011): $144500
A Richard, Chief, Hematology/oncology
Tufts Medical Centercity: Boston country: United States (us)
Grant 3T32CA009429-28S1 from National Cancer Institute
Abstract: This is a revised application from the William Dameshek Division of Hematology/Oncology at Tufts Medical Center for competitive renewal of our long-standing training grant, T32 CA09429, entitled "Research Training in Oncology". The long-term objective of the application has not changed, which is to continue the training and mentoring of physicians in the Hematology/Oncology Division Fellowship Program in basic and translational cancer science, in order to prepare them for independent careers in academic hematology/oncology. The program is based in the Division of Hematology/Oncology at Tufts Medical Center (Tufts MC), the principal teaching hospital for Tufts University School of Medicine (TUSM). The training program is a highly structured research experience that is centered around laboratory investigation within the research group of a faculty mentor. The laboratory component is complimented by formal coursework, other didactic training, and participation in seminars, workshops, and meetings. The progress of each trainee is closely monitored by a research committee. The Program currently has 26 research faculty mentors drawn from members of the Division and from other clinical and basic science departments at Tufts MC and TUSM, a significant increase from 19 Program faculty in the last competitive renewal in 2002. This reflects a new emphasis on cancer in the strategic plans of Tufts MC and TUSM, leading to the establishment of the Molecular Oncology Research Institute, and a major institutional effort to obtain National Cancer Institute Comprehensive Cancer Center designation for the Tufts Medical Center Cancer Center. The Program faculty mentors represent a major strength of the application, and are carefully selected on the basis of their training record and for their specific research interests in neoplasia, which span the spectrum from oncogenes and tumor suppressors, signal transduction, cell cycle regulation and apoptosis, angiogenesis and metastasis, animal models of hematologic malignancies and solid tumors, and preclinical testing of molecularly targeted cancer therapeutics. This training Program has been highly successful in preparing our fellows for careers in academic oncology. Former trainees now head major departments in academia and in NCI designated cancer centers, are on faculty at academic institutions in the US and elsewhere, and hold senior management positions in the oncology pharmaceutical field. RELEVANCE The treatment of cancer has been revolutionized over the past ten years through the development of drugs that specifically target cancer cells. The United States has a great need for cancer doctors who work at the interface between cancer patients and experimental treatments, and who can discover and apply the next generation of therapies. This grant application will support the training of such physicians at Tufts Medical Center, continuing a program that has generated leaders in this field for more than a quarter century
Keywords: oncology; Research Training
Project start date: 1981-09-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-08-226
3T32CA009429-28S1 (2011): $71419
5T32CA009429-28 (2011): $264130
COOPERATIVE MULTICENTER NEONATAL RESEARCH NETWORK
A Richard
Yale Universitycity: New Haven country: United States (us)
Grant 2U10HD027871-21 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Abstract: This Is a competitive renewal application to remain one of the cooperating study centers in the NICHD Cooperative Multicenter Neonatal Research Network. Neonatal-perinatal medicine has seen the introduction of a number of principles of management and innovative methodologies without rigorous use of the controlled observation necessary for their objective evaluation. A major problem has been the balance between assuring prompt implementation of new technologies, procedures, treatments and drugs, and adequate evaluation of their safety and efficacy. Because of the urgent demands of sick infants, care is often based upon limited knowledge of new modalities and, if the infant´s condition improves, the new treatment or procedure is frequently added to the arsenal of therapies before efficacy and/or safety have been sufficiently evaluated. The NICHD Cooperative Multicenter Neonatal Research Network was established to perform some of those critical studies and to change the culture of neonatology to one of evidence-based medicine. The goal of this project is to improve the practice of Newborn Medicine by the rigorous performance of multicenter clinical protocols. By working together, a network of academic medical centers will investigate the safety and efficacy of treatment and management strategies used in the care of newborn infants, especially extremely preterm infants. The evidence-based results will hopefully improve clinical practice
Keywords: Academic Medical Centers; Acute; adverse outcome; Apolipoprotein E; Asphyxia Neonatorum; base; Birth Weight; Breathing; Candidiasis; Caring; Clinical; clinical practice; Clinical Protocols; Clinical Research; Clinical Trials; Consent; Data Collection; Databases; design; DNA; Dose; Drug Kinetics; Early Diagnosis; early onset; Enrollment; Equilibrium; Escherichia coli; Ethnicity aspects; Evaluation; evidence base; Evidence Based Medicine; Extremely Low Birth Weight Infant; Faculty; falls; follow-up; Gender; Generic Drugs; Goals; Grant; Growth; Health system; high risk infant; Hospitals; Human; improved; induced hypothermia; Infant; Infant Care; innovation; Inositol; Investigation; Knowledge; Medicine; member; Methodology; Modality; Morbidity - disease rate; Mortality Vital Statistics; Multicenter Neonatal Research Network; National Institute of Child Health and Human Development; natural hypothermia; Neonatal; neonatal hypoxic-ischemic brain injury; Neonatal Intensive Care Units; neonate; Neonatology; new technology; Newborn Infant; Outcome; Patient Recruitments; Pediatric Hospitals; Performance; Perinatal; Pharmaceutical Preparations; Phototherapy; Premature Infant; pressure; Procedures; Protocols documentation; public health relevance; Publications; Pulse Oximetry; Race; Randomized Controlled Trials; randomized trial; Registries; Reporting; Research Activity; Research Personnel; Research Subjects; Safety; Sampling; Sampling Studies; Sepsis; Serum; sex; Site; surfactant; surveillance study; Survivors; Treatment Efficacy; Very Low Birth Weight Infant; Work
Project start date: 1991-04-01
Project end date: 2013-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: RFA-HD-10-003
2U10HD027871-21 (2011): $8275
AEROBIC EXERCISE TO IMPROVE OUTCOMES OF TREATMENT FOR METHAMPHETAMINE DEPENDENCE
A Richard, Professor In Residence
University Of California Los Angelescity: Los Angeles country: United States (us)
Grant 5R01DA027633-03 from National Institute On Drug Abuse
Abstract: This five-year study will assemble data on the efficacy of aerobic exercise for the treatment of methamphetamine dependence in a population of 150 individuals seeking treatment at Cri-Help residential drug treatment program in Los Angles. After signing consent and satisfying all inclusion/exclusion requirements, participants will be enrolled into the study and undergo baseline assessments during approximately two weeks of treatment as usual. After randomization, participants will enter the Exercise condition (n=75) or the control (Health Education; n=75) condition for an 8-week intervention duration. Incentives for participation in either condition activity (thrice weekly) are fixed at $10 per session. Of the 150 total participants, 30 voluntary participants will be part of a brain imaging substudy. The objective of the imaging substudy is to determine possible brain mechanisms associated with hypothesized effects of exercise on treatment outcomes. The primary goal of the study is to rigorously and comprehensively determine whether inclusion of a aerobic exercise within a residential program improves treatment outcomes in terms of reduced methamphetamine use during the first 12 weeks post discharge and 26 week follow up, as well as to characterize effects of exercise on health, psychiatric symptoms and cognition compared to the control (education) group pre/post intervention. Aims of the study are Aim 1. To characterize effects of an aerobic exercise intervention ("Exercise") compared to health education ("Education") in terms of drug use after discharge from residential drug treatment in a population of MA- dependent individuals. Aim 2. To characterize effects of Exercise on MA craving and negative affective states including anxiety, depression, anhedonia, and stress reactivity among participants in residential treatment for MA dependence. Aim 3. To characterize effects of Exercise on neurocognitive functioning. Aim 4. To characterize variations in health-related outcomes among participants in the Exercise condition compared with those in the Education condition. Aim 5. To examine changes in dopamine D2/D3 receptor availability in abstinent MA-dependent participants assigned to an Exercise group compared to a subsample of participants in an Education (control) group (n = 15 per group). Aim 6. To examine differences in addiction-related behaviors (per ASI-type measures) according to intervention condition. There is a critical need for systematic evaluation of strategies for treating methamphetamine use disorders. Thus, this project responds to NIDA request (RFA-DA-09-013) to develop and evaluate an effective exercise-based intervention for addiction. The proposed research is of considerable public health significance in that it will provide foundational information on aerobic exercise as an intervention for methamphetamine dependence, a serious drug problem with extensive impacts. If proven effective, the protocol could be useful in treating addiction and in reducing methamphetamine use among treated individuals, thereby efficiently reducing drug abuse and related consequences such as criminal activity, social disruption, and elevated risk of HIV transmission/infection due to increased frequency of unsafe sexual activities while on methamphetamine. The proposed project will determine clinical utility of an innovative intervention protocol previously untested in MA-dependent individuals
Keywords: addiction; Address; Aerobic Exercise; Affective; Anhedonia; Anxiety; base; Behavior; Behavior Therapy; Behavioral; Blood Pressure; Brain; Brain imaging; Caring; Cholesterol; Clinical; Cognition; Consent; Control Groups; craving; Crime; Data; Data Quality; design; Disease; Dopamine; Drug abuse; Drug usage; Educational aspects; Employment; Enrollment; Evaluation; evidence base; Exclusion; Exercise; follow-up; Frequencies (time pattern); Goals; Health; Health education; high risk sexual behavior; HIV; Image; improved; Incentives; Individual; Infection; innovation; Intervention; Measures; Medical; meetings; Mental Depression; Methamphetamine; Methamphetamine dependence; National Institute of Drug Abuse; Neurocognitive; Outcome; Participant; Patient Self-Report; Pharmaceutical Preparations; Pharmacotherapy; Physical activity; Population; post intervention; Preclinical Drug Evaluation; prevent; Prevention; programs; Protocols documentation; public health medicine (field); public health relevance; Randomized; receptor; Recovery; Relapse; remediation; Research; Residential Treatment; response; Risk; Sampling; Science; Sex Behavior; social; Social Behavior; Stress; Symptoms; transmission process; treatment as usual; Treatment outcome; treatment program; treatment response; treatment strategy; Urine; Variant; Weight
Relevance: Relevance to Public Health. The proposed research is of considerable public health significance in that it will provide foundational information on aerobic exercise as an intervention for methamphetamine dependence, a serious drug problem with extensive impacts. If proven effective, the protocol could be useful in treating addiction and in reducing methamphetamine use among treated individuals, thereby efficiently reducing drug abuse and related consequences such as criminal activity, social disruption, and elevated risk of HIV transmission/infection due to increased frequency of unsafe sexual activities while on methamphetamine. The proposed project will determine clinical utility of an innovative intervention protocol previously untested in MA-dependent individuals
Project start date: 2009-09-30
Project end date: 2014-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: RFA-DA-09-013
5R01DA027633-03 (2011): $517671
VISUAL/SPATIAL PROPERTIES OF POSTERIOR PARIETAL NEURONS
A Richard
California Institute Of Technologycity: Pasadena country: United States (us)
Grant 3R01EY005522-30S1 from National Eye Institute
Abstract: This Competitive Revision is submitted in response to the notice NOT-OD-09-058 NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. This application expands the scope and the methodology of the parent grant "Visual/Spatial Properties of Posterior Parietal Neurons" to include two additional research aims. Most of the current knowledge about neural mechanisms underlying eye-hand coordination and selection of movement plans has been derived from electrophysiological recordings in non-human primates, and more recently from fMRI experiments in humans. In order to be able to integrate those findings, it is necessary to study both species by means of the same method, especially because results from the two techniques have not always led to the same conclusions. The current grant revision aims to elucidate the discrepancy between monkey and human studies concerning the degree of overlap between hand and eye signals within the frontoparietal network. Specifically, we will investigate how spatial and effector choices are represented in the monkey brain by applying event-related fMRI while monkeys are choosing either between spatial target positions (i.e. left vs. right) or between different effectors (i.e. eye vs. hand). In addition, we will expand ongoing neurophysiological experiments by investigating how spatial choice preferences originating either from internal or external factors are represented by different areas in the brain. This revision adheres to the goals of the Recovery Act. It will entail retaining a current senior postdoc employee, hiring a new postdoc, a new technician, and a new part-time RF engineer. It will invest in the new technology essential to expand the goals of the project, by acquiring advanced MR-compatible equipment from domestic companies. The results of the proposed studies can be used to help design therapies for patients suffering from damage to frontal and parietal cortex from strokes and traumatic brain injuries. Application of functional imaging in monkeys, as routinely is done in human patients and healthy subjects, will facilitate the understanding of normal cortical functions and deficits that result from neurological diseases, and can guide the diagnoses and treatments for these diseases
Keywords: Area; Attention; base; Behavior; Behavioral; Brain; Cognitive; Contralateral; Coupled; Cues; Data; Data Analyses; Decision Making; Diagnosis; Disease; Employee; Engineering; Equipment; Evaluation; Event; Exhibits; Eye; eye hand coordination; flexibility; Functional Imaging; Functional Magnetic Resonance Imaging; Funding; Goals; Grant; Hand; Human; Individual; insight; Joystick; Knowledge; Left; Lip structure; Location; Magnetic Resonance Imaging; memory encoding; Methodology; Methods; Modeling; Monkeys; Motor; Motor output; Movement; nervous system disorder; neuromechanism; Neurons; neurophysiology; new technology; nonhuman primate; novel; parent grant; Parietal; Parietal Lobe; Patients; Population; Positioning Attribute; Postdoctoral Fellow; preference; Primates; Process; Property; prospective; public health medicine (field); public health relevance; Recovery; relating to nervous system; Research; research study; response; Rewards; Role; Saccades; Schedule; segregation; Sensory; Signal Transduction; Staging; stroke; Techniques; Testing; therapy design; Time; Traumatic Brain Injury; United States National Institutes of Health; Upper arm; Variant; virtual; Visual; Visual Cortex; visual motor; Visuospatial
Relevance: Relevance to public health statement The results of the proposed studies can be used to help design therapies for patients suffering from damage to frontal and parietal cortex from strokes and traumatic brain injuries. Application of functional imaging in monkeys, as routinely is done in human patients and healthy subjects, will facilitate the understanding of normal cortical functions and deficits that result from neurological diseases, and can guide the diagnoses and treatments for these diseases
Project start date: 1994-03-01
Project end date: 2012-09-29
Budget start date: 30-SEP-2009
Budget end date: 29-SEP-2012
PFA/PA: PA-07-070
3R01EY005522-30S1 (2009): $751446
Sponsored Links Excellgen http://Excellgen.com
GENOMIC APPROACHES TO COMMON CHRONIC DISEASE
A Richard
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Abstract: This center program seeks to evaluate the performance of genomic sequence information for predicting health and disease above and beyond traditional risk factors. To accomplish this objective we will develop statistical strategies to 1) determine which DMA sequence variations combine to improve the prediction of disease beyond the traditional risk factors in which subsets of a particular population, 2) validate the resultant multiplicity of models in the population of inference and 3) test the generalizability of the validated models in an independent population. The proposed study includes 1) capturing comprehensive DNA sequence variation in a network of genes that have been hypothesized to contribute to risk of cardiovascular disease and establish how their organization propagates constraints on genetic studies of a common chronic multifactorial disease, 2) developing non-traditional statistical methods for reducing the high dimensional network of genetic and environmental agents into subsets sufficient for predicting the network of intermediate traits that connect the genome with disease endpoints, 3) developing non-traditional statistical methods for reducing the high dimensional network of genetic and environmental agents into subsets sufficient for estimating the contribution of the network of DNA sequence variations to the prediction of disease endpoints in the population at large beyond the contribution of the network of intermediate biochemical and physiological traits and established risk factors and 4) estimating the relative roles of rare DNA sequence variations, common DNA sequence variations and rare combinations of common variations in explaining incident cases of CHD in the population at large. Co-investigators involved in this center program bring to this research endeavor expertise in genetics, statistics, molecular biology and medicine that is a consequence of 20+ years of collaborative research on complex common diseases of humans. Each of the co-investigators has decades of experience in teaching at the undergraduate and graduate level. One of the objectives of our renewal application will be to disseminate expert knowledge to the wider academic community about the most advanced measurement technologies and computation/statistical methods being used in carrying out a systems approach to genetic studies of common chronic diseases. To this end, we will implement a short course entitled "Genomic Approaches to Common Chronic Disease Research" to introduce systems biology research to advanced undergraduate and beginning graduate level students and offer a 10 week internship in the laboratory of one of the participating co-investigators
Keywords: Biochemical; cardiovascular disorder risk; Chronic; Chronic Disease; Communities; Complex; Disease; DNA Sequence; Educational process of instructing; environmental agent; experience; Genes; Genetic; Genome; Genomics; Health; human disease; improved; Internships; Knowledge; Laboratories; Measurement; Modeling; Molecular Biology; Molecular Medicine; Performance; Physiological; Platelet Factor 4; Population; programs; Relative (related person); Research; Research Personnel; Risk Factors; Role; Statistical Methods; statistics; Students; System; Systems Biology; Technology; Testing; trait; Variant
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
5P50GM065509-10_0007 (2011): $473637
VISUAL/SPATIAL PROPERTIES OF POSTERIOR PARIETAL NEURONS
A Richard
California Institute Of Technologycity: Pasadena country: United States (us)
Grant 5R01EY005522-32 from National Eye Institute
Abstract: This application is to study how sensory-motor transformations are accomplished in the cerebral cortex. In particular we will examine how spatial information is represented in cortex (Aim 1) and how coordinate transformations are accomplished between these representations (Aim 2). Previous work on these topics has examined how space is represented for achieving the movement of a single effector, for instance the eyes or the hand. However, movements generally involve multiple effectors and typically include hand-eye and bimanual movements. In Aim 1 we will advance a new finding, made in dorsal premotor cortex (PMd) during the last grant period, of a relative coding of the position of the hand, eyes and goal of a reach. This aim will test several new aspects and implications of relative coding. (1) It will examine the extent of relative coding in other areas of the sensorimotor pathway including area 5 and primary motor cortex. {2) It will determine if the 2 limbs also show a relative coding in cortical areas involved in reaching. Such a result would indicate that relative coding may be general mechanism for movements involving multiple body parts. (3) It will examine if relative coding of the hand is state dependent in PMd, and changes depending on the task, or if it is "hard wired". (4) It will determine if eye movement areas also show a relative coding of the eye and hand for eye movement tasks, which made facilitate eye- hand coordination. (5) It will directly test the hypothesis that relative coding, by its nature, is translation (and perhaps rotation) invariant across the workspace. In Aim 2 we will examine the gain field mechanism that is thought to be responsible for coordinate transformations between representations. (1) This aim will determine if gain fields exist simultaneously with relative position encoding. (2) It will determine whether gain fields in particular areas of cortex are concerned with extrinsic space around the body or intrinsic space within the body. 3) The mathematical mechanism for gain modulation will be determined. We will distinguish whether it is a pure multiplication of inputs or a function which approximates multiplication such as non-linear addition. Since gain fields are believed to be a general mechanism for neural computation, the results of these studies should have broad applicability to understanding neural processing beyond coordinate transformations. The results of the proposed studies can be used to help design therapies for patients suffering from damage to frontal and parietal cortex from strokes and traumatic brain injuries. They will help in understanding deficits that result from neurological diseases that effect cortical functioning, and can guide the diagnoses and treatments for these diseases
Keywords: Accounting; Area; Behavior; Body part; Brain; Brain Stem; Cerebral cortex; Code; Complex; Computer Simulation; computer studies; design; Diagnosis; Disease; Dorsal; Eye; eye hand coordination; Eye Movements; frontal eye fields; frontal lobe; gaze; Goals; Grant; Hand; insight; Joints; Knowledge; lateral intraparietal area; Limb structure; Location; Methods; Motor; Motor Cortex; Motor output; Movement; Muscle; Nature; nerve supply; nervous system disorder; neuromechanism; Neurons; novel; Parietal; Parietal Lobe; Pathway interactions; Patients; Positioning Attribute; Posture; Process; programs; Property; relating to nervous system; Relative (related person); Reporting; Research; Research Personnel; research study; response; Rotation; Saccades; Sensory; Signal Transduction; Staging; stroke; System; Testing; therapy design; Translations; Traumatic Brain Injury; visual motor; Visuospatial; Work
Project start date: 1994-03-01
Project end date: 2012-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
5R01EY005522-32 (2011): $512968
5R01EY005522-31 (2010): $518780
PLANNING IN PARIETAL-FRONTAL CIRCUITS
A Richard
California Institute Of Technologycity: Pasadena country: United States (us)
Grant 5R01EY007492-21 from National Eye Institute
Abstract: This application is to study effector choice in parietal-frontal circuits. It focuses on movement plans and decisions regarding which part of the body to use to obtain a goal. Although this is a very common behavior and important for daily activities such as typing, playing musical instruments, sports, and operating an automobile, to our knowledge effector choice has generally not been studied at the neuronal level. Aim 1 will examine 2 models of cortical processing for effector selectivity. The parallel model hypothesizes that all cortical areas that represent potential movement plans before selection are the same areas that represent the outcomes of those decisions. The serial model hypothesizes that some cortical areas represent potential plans and outcomes and later cortical areas only represent the outcomes. Aim 2 will examine the dorsal premotor cortex (PMd) to see if it is similar to the parietal reach region (PRR) in representing both potential plans and outcomes. It will also determine whether PMd cells are mostly selective for reach outcomes (like PRR) or if it contains a mixture of reach and saccade selective neurons. The latter finding would suggest that PMd may be further along in the pathway for hand-eye coordination than PRR, which is suggested by other recent studies examining coordinate frames. Although PRR and the lateral intraparietal area (LIP) have recently been found to have activity consistent with their representing potential plans and outcomes of effector decisions, there is no evidence that they are actually necessary for effector decision making. Aim 3 will test whether LIP and PRR are necessary by inactivating them during effector decision making. If inactivation of these two areas produce a bias in the decision task (LIP for saccades and PRR for reaches), then these areas would be within the network for effector decision making. The three aims will provide important new information regarding how effector planning and decisions are processed including the functional hierarchy of the areas involved (Aim 1), the role of dorsal premotor cortex (Aim 2), and whether areas in the parietal cortex are involved in the decision process or only reflect the potential plans and the outcome of the decision (Aim 3). Results from this study can be used to help design therapies for patients suffering from damage to frontal and parietal cortex from strokes and traumatic brain injuries. They will help in understanding deficits that result from neurological diseases that effect cortical functioning, and in guiding diagnoses and treatments for these diseases. They will also be useful for guiding the design of neural prosthetics. By determining the types of signals that can be obtained from different brain regions, neural implants can be made to read out these signals in order to control assistive external devices for paralyzed patients
Keywords: Animals; Area; Attention; Automobiles; Behavior; Behavioral; Body part; Brain region; Categories; Cells; Code; Decision Making; design; Devices; Diagnosis; Disease; Dorsal; Eye; eye hand coordination; Eye Movements; Fingers; foot; frontal lobe; Goals; Grant; Hand; Hybrids; Implant; insight; instrument; lateral intraparietal area; Location; Modeling; Motor; Motor Cortex; Movement; nervous system disorder; neural circuit; neural prosthesis; Neurons; Outcome; Paralysed; Parietal; Parietal Lobe; parietal-frontal circuits; Pathway interactions; Patients; Play; Population; Probability; Process; public health relevance; Reading; relating to nervous system; Research; research study; Rewards; Role; Saccades; Sensory; sensory integration; Signal Transduction; Soccer; Specificity; Sports; Staging; stroke; Testing; therapy design; Traumatic Brain Injury
Relevance: Results from this study can be used to help design therapies for patients suffering from damage to frontal and parietal cortex from strokes and traumatic brain injuries. They will help in understanding deficits that result from neurological diseases that effect cortical functioning, and in guiding diagnoses and treatments for these diseases. They will also be useful for guiding the design of neural prosthetics. By determining the types of signals that can be obtained from different brain regions, neural implants can be made to read out these signals in order to control assistive external devices for paralyzed patients
Project start date: 1987-09-01
Project end date: 2014-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-07-070
5R01EY007492-21 (2011): $388800
MOLECULAR, CELLULAR AND SYSTEMS NEUROSCIENCE
A Richard
California Institute Of Technologycity: Pasadena country: United States (us)
Grant 5T32NS007251-24 from National Institute Of Neurological Disorders And Stroke
Abstract: This application is to continue the Postdoctoral Program in the Neurosciences at the Molecular Cellular, and Systems levels at the California Institute of Technology. This program is in its 20th year and has been highly successful in training a generation of Neuroscientists. The program involves 22 faculty members whose main research area is Neuroscience. Two new Neurobiology faculty members were appointed during the last period of the grant. Due to the tremendous growth in neuroscience research at Caltech, we are requesting an increase in the level of the program to fund six trainees per year rather than the four of the past. Topics of training in the program include 1) sensory systems including the auditory, visual and olfactory systems, 2) sensory-motor integration, 3) the cellular and molecular basis of synaptic transmission, 4) neural mechanisms of learning and plasticity, 5) neural development, cell lineage and differentiation, 6) theoretical neurobiology and computational modeling of neural systems and 7) reward systems. Additional and new directions of the program include 1) application of molecular techniques to understanding behavior, 2) translational research with medical relevance, and 3) theoretical neurobiology, 4) brain imaging across species including humans, non-human primates, and rodents, and 5) neurophysiological studies of neural populations using multicellular recordings. These studies will lead to the understanding and translation of research toward developing cures for a variety of neurological diseases including Alzheimer´s Disease, Parkinsonism, learning disabilities, aging, vision and hearing deficits, paralysis, strokes, and drug and alcohol dependency. The primary mission is to train scientists for fruitful, successful careers in neurobiological research. Trainees hold Ph.D. or M.D. degrees and have daily contact with the research sponsor. The duration of the training period is usually two years with occasional extensions to three years when warranted. Research related activities such as seminars, journal clubs, and collaborative research through the CNS Program, the Sloan-Swartz Center, the Broad Fellows Program, Information Science and Technology, and the Beckman Institute afford a rich training experience. Also included in the program will be instruction in responsible conduct of research. Special efforts will be made to attract more minority trainees to the program through several approaches at all levels of education. These efforts include extensive involvement of the faculty in recruitment. In the current group of eligible postdoctoral fellows associated with the training faculty 13.5% are from underrepresented minorities. The neuroscience laboratories are well equipped and occupy six buildings on the Caltech campus. There are many special resources available to the postdoctoral trainees which include facilities for monoclonal antibody production, transgenic mice study, MRI and optical imaging, primate behavior and electrophysiology, equipment fabrication, computer modeling, electronic circuit design and manufacture, electron microscopy, synthesis and sequencing of proteins and genes, cell sorting, cell culture, and cell electrophysiology
Keywords: Molecular; Neurosciences; System
Project start date: 1996-09-30
Project end date: 2012-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
5T32NS007251-24 (2010): $207108
CELLULAR AND MOLECULAR BIOLOGY OF AGING
A Richard, Professor
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 5P30AG013283-17 from National Institute On Aging
Abstract: The University of Michigan requests funding for Years 16 - 20 of our Nathan Shock Center. UM receives more NIA funding than any other institution, and 48 grants in the biology of aging provide $10.4m/year in annual funding. Our Center´s 2006 move to the new BSR building provided 21,000 square feet for Biogerontology, and allowed recruitment of four new tenure track researchers studying aging in mice, flies, and worms. The NSC Administrative Core will be led by Richard A. Miller, who will also serve as the Center Director. This core will facilitate communication among biogerontologists at UM and at other institutions, and take responsibility for advisory committees, interaction with UM and NIH officials, and supervision of an animal resource sharing website. The Research Development Core, headed by Susan Brooks, will administer a pilot grants program, organize an annual conference on a topic in aging research, and provide mentoring and financial support for a select group of junior faculty scientists. The Aging Rodent Core, led by Evan Keller, will support production of new transgenic and knockout mice, pay per diem costs to allow scientists to raise mice to old ages, and contribute to the costs of histopathologic analyses in the context of lifespan studies. The Drosophila Aging Core, directed by Scott Pletcher, will provide specialized equipment and validated protocols to support studies of aging, in flies, by experienced Drosophila geneticists new to aging, and by gerontologists who are just starting to incorporate Drosophila into their program. The Comparative Biogerontology Core, headed by Richard Miller, will create and characterize short-term primary fibroblast cells from a wide range of short-lived and long-lived rodents, primates, bats, birds, and dogs, and stimulate research at UM and elsewhere into cellular traits correlated with longevity across species. The Functional Assessment Core, directed by Greg Cartee, will provide advice and financial assistance to UM scientists who wish to make use of UM´s exceptionally rich set of biomedical service core laboratories, to help Shock Center scientists, especially junior faculty members, introduce advanced methodologies into their research programs, including work on aims that might otherwise be deemed too risky or ambitious to tackle
Keywords: Advisory Committees; Age; age related; Aging; Alzheimer`s Disease; American; animal resource; Animals; Area; Arts; Athletic; base; Biological; Biology; Biology of Aging; Biomedical Research; Birds; bone; Canis familiaris; Care given by nurses; Cells; Chiroptera; Clinical; college; Commit; Communication; Communities; comparative; Core Facility; cost; Country; design; Developmental Cell Biology; Direct Costs; Discipline; Disease; Drosophila genus; Educational aspects; Elderly; Enrollment; Equipment; experience; Extramural Activities; Faculty; Fibroblasts; Financial Support; Floor; fly; Funding; Geriatric Nursing; Geriatrics; germ free condition; Gerontology; Grant; Head; Health; Hearing; Housing; immunopathology; Individual; insight; Institutes; Institution; Interdisciplinary Study; Journals; Knockout Mice; Laboratories; Laboratory Research; Leadership; Libraries; Life; London; Longevity; medical schools; member; Mentors; Metabolism; Methodology; Michigan; Molecular; Molecular Medicine; Mus; National Institute on Aging; Neurosciences; news; Online Systems; Orthopedics; Outcome Study; Positioning Attribute; prevent; Primates; Procedures; Production; programs; Protocols documentation; public health medicine (field); Reporting; Research; research and development; research facility; Research Personnel; Research Project Grants; Research Support; Research Training; Resource Sharing; Resources; Rest; Rewards; Rodent; Role; Scholarship; Schools; Science; Scientist; Services; Shock; Specific Pathogen Frees; square foot; stem cell biology; Students; Supervision; Surveys; symposium; Testing; Time; Training; trait; Transgenic Mice; United States; United States National Institutes of Health; Universities; Walking; web site; Work
Relevance: The UM Nathan Shock Center will suppport a wide range of research projects on fundamental questions in the biology of aging. The outcome of these studies may offer new Insights into strategies to prevent disease and maintain excellent health at older ages
Project start date: 1997-07-15
Project end date: 2015-06-30
Budget start date: 1-SEP-2011
Budget end date: 30-JUN-2012
PFA/PA: RFA-AG-10-009
5P30AG013283-17 (2011): $581815
ROLES OF CDC42 AND ITS SIGNALING PARTNERS IN CELL GROWTH AND DIFFERENTIATION
A Richard, Professor
Cornell University Ithacacity: Ithaca country: United States (us)
Grant 5R01GM047458-20 from National Institute Of General Medical Sciences
Abstract: The Ras-related GTPase Cdc42 plays important roles in a wide range of cellular processes including the establishment of cell polarity and the control of cell growth and migration. The proper regulation of Cdc42- coupled signaling activities is crucial for its cellular functions, as evidenced by the hyper-activation of Cdc42 by oncogenic guanine nucleotide exchange factors (GEFs), or mutations that give rise to an accelerated exchange of GDP for GTP, resulting in cellular transformation and tumor formation in nude mice. During the past funding period, we established how Cdc42 and its regulatory protein Cool-1 (for Cloned-out of library), which functions both as a GEF and a target/effector for Cdc42, regulate cell growth by helping to maintain proper EGF receptor (EGFR) homeostasis. We also discovered that the phosphorylation-dephosphorylation cycle of Cool-1 influences cell migration, raising the interesting possibility that Cdc42 and its signaling partners may coordinate cell growth control with the regulation of cell motility. Moreover, our studies with different cell and genetic model systems have highlighted a role for Cdc42 in cellular differentiation and cell fate determination. In the coming funding period, we will continue to combine biochemical and structural biology-based studies with genetic approaches to extend these findings and better establish how Cdc42 and its regulatory proteins impact three fundamentally important cellular processes, namely cell growth, migration, and differentiation. These studies will constitute 3 specific lines of investigation. 1) Determine how Cdc42 and its signaling partners work together to maintain proper EGFR homeostasis. In these studies, we will be particularly interested in determining the regulatory cues that set the timing for the Cdc42- mediated signals that establish the proper balance between EGFR-coupled mitogenic signaling versus receptor down-regulation and degradation. 2.) Examine how Cool-1 and its binding partners regulate cell migration. Here, we will follow-up recent clues suggesting that the phosphorylation of Cool-1 stimulates its dissociation from Cat (for Cool-associated tyrosine kinase substrate) and helps trigger the disassembly of focal complexes. We also will want to see whether the Cdc42-GEF activity of Cool-1, which is triggered by its phosphorylation, confers important regulatory effects on cell migration. 3.) Examine the roles of Cdc42 and its signaling partners in cellular differentiation. We will explore the possible involvement of Cdc42 in ensuring the proper lifetime for signaling activities necessary for neuronal differentiation. In addition, we will build on our recent studies in mouse embryonic (P19) cells that suggest Cdc42 and a dual function Cdc42- GEF/target-effector that we recently discovered, play important roles in neurogenesis. We expect that these studies will yield new insights into how Cdc42 is able to mediate a diversity of cellular responses that are necessary for normal biological outcomes and, when de-regulated, gives rise to a variety of disease states including cancer and neurodegenerative disorders
Keywords: Back; base; Binding (Molecular Function); Biochemical; Biochemical Genetics; Biological; Biological Models; Brain; Cell Differentiation process; cell growth; Cell Line; Cell Lineage; Cell model; cell motility; Cell physiology; Cell Polarity; Cells; Coat Protein Complex I; Complement; Complex; Coupled; Cues; Development; Disease; Dissociation; EGF gene; Embryo; Endocytosis; Ensure; Epidermal Growth Factor Receptor; Equilibrium; Event; Excision; feeding; Felis catus; follow-up; Funding; Genetic; Genetic Models; genetic regulatory protein; Goals; Growth; Growth Factor Receptors; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate; Guanosine Triphosphate Phosphohydrolases; Homeostasis; insight; Integrins; interest; Investigation; Laboratories; Learning; Libraries; Link; Malignant Neoplasms; Mediating; member; metaplastic cell transformation; migration; Molecular; Morphogenesis; mouse development; Movement; Mus; mutant; Mutation; Names; Nerve; Neurites; Neurodegenerative Disorders; neurogenesis; Neuronal Differentiation; Neurons; novel; Nude Mice; olfactory lobe; Oncogenic; Outcome; PC12 Cells; Pheochromocytoma; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Process; programs; Protein Dephosphorylation; Protein Family; Protein Tyrosine Kinase; Proteins; PTK2 gene; ras-Related G-Proteins; Rattus; receptor; receptor coupling; Receptor Down-Regulation; Receptor Signaling; Regulation; Research Personnel; response; rhoB p20 GDI; Role; Signal Pathway; Signal Transduction; structural biology; Teratoma; Testing; Time; trafficking; tumor; Tyrosine Phosphorylation; Ubiquitination; Work; Wound Healing; X-Linked Mental Retardation
Project start date: 1992-05-01
Project end date: 2012-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
5R01GM047458-20 (2011): $288149
RESEARCH TRAINING IN ALIMENTARY TRACT SURGERY
A Richard, Professor
Massachusetts General Hospitalcity: Boston country: United States (us)
Grant 5T32DK007754-13 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: The rapid changes that have occurred in Gl surgery over the past decade have created a unique opportunity for the creation of new knowledge, and yet our training programs have not appropriately adapted to this changing reality. This T32 Program has been designed to train the next generation of academic Gl surgeons through a continued focus in the basic science field and an expanded focus on clinical research and surgical innovation, two research fields that have thus far been lacking when it comes to scientific rigor. The enormous resources and talented personnel in the Harvard Medical School community have been leveraged to create a unique environment for the research training of our future academic Gl surgeons. First funded in 1997 as a collaboration between the Departments of Surgery at the Brigham and Women´s Hospital and the former Beth Israel Hospital, this program has been expanded to include investigators from all three major adult teaching hospital affiliates of Harvard Medical School (BIDMC, BWH, MGH). It is clear that a major impediment to promoting and maintaining high quality Gl surgical research has been the "silo" effect, whereby investigators from various disciplines function as independent entities with little or no interaction. Accordingly, this T32 program will be comprised of three research tracks (1) Basic Science, (2) Clinical Research/Outcomes and (3) Surgical Technology/Innovation. The Program has been designed to bring surgeon-scientists together from these three different investigative disciplines, establishing a unique environment for collaboration and interaction. The Training Program Executive Committee (Hodin, Soybel, Hasselgren) will oversee the selection of trainees, designation of preceptors, prescription of formal coursework, and participation in programs teaching ethics and the responsible conduct in research. The Program is open to surgical residents or fellows in accredited U.S. Residency Programs and a pro-active process is in place to seek applications from individuals belonging to under-represented minority groups. This T32 Program is therefore designed to provide intensive, coordinated research training with the goal of preparing individuals to become independently funded investigators in the field of alimentary tract surgery. A large number of gastrointestinal (Gl) diseases are best treated through surgery. It is therefore imperative that surgeons be appropriately trained to perform research that will advance our knowledge of Gl diseases. This Program is designed to provide superb training to young surgeons so that they are able to pursue careers that will focus on improving the life of patients suffering from Gl diseases
Keywords: Gastrointestinal tract structure; Operative Surgical Procedures; Research Training
Project start date: 1997-07-18
Project end date: 2014-06-30
Budget start date: 1-JUL-2011
Budget end date: 30-JUN-2012
PFA/PA: PA-06-468
5T32DK007754-13 (2011): $233372
NEURAL PROSTHESIS USING POSTERIOR PARIETAL REACH REGION
A Richard
California Institute Of Technologycity: Pasadena country: United States (us)
Grant 5R01EY013337-10 from National Eye Institute
Abstract: The purpose of this application is to explore how high level planning signals can be used for control of neural prosthetics to assist paralyzed patients. This study has both scientific and engineering components. The scientific investigations entail exploring how cognitive signals related to movement intentions are encoded in the parietal-frontal circuits. The engineering component will be guided by the scientific findings to best design and tailor algorithms for decoding these cognitive signals. Areas of algorithmic development include new signal processing and feature extraction techniques, extensions of Bayesian classification and Kalman filtering algorithms, and new applications of speech recognition and finite state machine techniques. Aim 1 will examine how the goals of reach movements are represented in 3 dimensions in the parietal reach region (PRR) and the dorsal premotor cortex (PMd) and develop decode algorithms to control the location of a cursor using these signals (so-called brain-control task). Goal decoding has the attributes of being very versatile and rapid for prosthetics applications. This aim will also determine if goal locations can be decoded using local field potentials (LFPs) rather than spike activity using advanced signal processing techniques. An advantage of LFPs for prosthetics is their ease and longevity of recording. Aim 2 will examine whether neural activity in PRR and PMd predicts the current location of the limb during trajectory movements, and if this "forward model" can be used to generate trajectories in brain control tasks. Techniques suited for continuously varying dynamic systems will be applied to decoding the trajectories. Aim 3 will study plasticity in PRR and PMd related to context, learning and reward. In this aim we will examine how the ability of the brain to learn and adapt can lead to better performance of brain-machine interfaces. Aim 4 will examine the very challenging situation of decoding movement plans continuously. Studies in this field generally use event markers derived from the trials of a task to assist decoding. However, these markers will not exist for clinical applications of prosthetics and the problem of recognizing and interpreting neural signals becomes much more challenging. We will apply and extend techniques from speech recognition and finite state machines to this problem. In particular, we will examine how eye movement information during natural hand-eye coordination can help decode reach movements from neural activity. This eye movement information will be derived from eye movement recordings and from the recording of neural signals related to eye movements. Knowledge from this work will be applied to brain- control tasks involving the continuous, sequential determination of goals
Keywords: 3-Dimensional; ing; Algorithms; Animals; Area; base; Behavioral; Brain; brain machine interface; Classification; clinical application; Cognitive; computerized data processing; Computers; Control Animal; design; Development; Dimensions; Dorsal; Engineering; Environment; Event; expectation; Eye; eye hand coordination; Eye Movements; gaze; Goals; Grant; Implant; improved; Intention; Investigation; Knowledge; Lead; Learning; Limb structure; Location; Longevity; Maps; Methods; mind control; Modeling; Monitor; Monkeys; Moods; Motivation; Movement; Nature; neural prosthesis; Neurons; Paralysed; Parietal; parietal-frontal circuits; Patient Preferences; Patients; Pattern; Performance; Positioning Attribute; Process; Prosthesis; relating to nervous system; Research; research study; response; Rewards; Robotics; Scanning; Self-Help Devices; Signal Transduction; speech recognition; success; System; Techniques; Testing; Time; Visual; Work
Project start date: 2001-02-01
Project end date: 2011-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
5R01EY013337-10 (2010): $404887
3R01EY013337-09S1 (2009): $310254
Sponsored Links Excellgen http://Excellgen.com
RESEARCH TRAINING IN BIOGERONTOLOGY
A Richard, Professor
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 5T32AG000114-27 from National Institute On Aging
Abstract: The proposed program, "Research Training in Biogerontology," seeks a five-year continuation (-26 to -30) of our current award, a grant originally funded in 1985 and supported through April of 2010. Funds to support 6 predoctoral and 3 postdoctoral trainees are requested, matching current program size. This Program is situated within a Geriatrics Center that provides an exceptionally rich intellectual environment for research and training in the biology of aging, through its dedicated research space, Pepper Center, Nathan Shock Center, and GRECC core grants, multiple NIA-funded R01, U01, and P01 grants, and recent recruitment of new faculty. The Preceptor group includes 23 well-funded faculty members from 15 departments. The main goal of the Training Program is to select, train and prepare graduate students and postdoctoral fellows for careers as leaders in biological and biomedical aging research. Predoctoral trainees are accepted into the program only after they have completed departmental course requirements and embarked on full-time research programs. The main activity of each predoctoral and postdoctoral trainee is the development of a faculty-supervised research project leading to discoveries and peer-reviewed publications on important questions in the biology of aging. Trainee research projects are also expected to meet the highest professional standards in cognate disciplines of neuroscience, genetics, cell biology, biochemistry, immunology and physiology. In addition to discipline-specific training provided by the mentor and department, each trainee also benefits from Training Program activities that provide deep and broad background in modern aging research. These include a biweekly research series in which faculty presentations alternate with trainee research-in-progress talks; a monthly journal club; participation in Shock and Pepper Center annual research retreats; presentations at the annual Geriatrics Center research symposium; and opportunities to interact with guest speakers who visit each year to discuss topics in aging and geriatrics. Trainees also benefit from the University´s well-established resources for training in the responsible conduct of research. The physical resources available to trainees through the Geriatrics Center and the University are outstanding, and include over 17,000 sq. ft. of wet lab space in the newly opened Biomedical Sciences Research Building, as well as the Medical Center´s many sophisticated technical core facilities. High quality training in the biology of aging will prepare students and trainees for outstanding careers at the forefront of Biogerontology, helping them make discoveries in the relation of aging to the diseases that afflict people in the second half of their lifespan
Keywords: Gerontology; Research Training
Project start date: 1985-09-01
Project end date: 2015-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-08-226
5T32AG000114-27 (2011): $403841
INFANT STUDY OF INHALED SALINE IN CYSTIC FIBROSIS (ISIS) - DCC
A Richard
University Of Washingtoncity: Seattle country: United States (us)
Grant 5U01HL092932-04 from National Heart, Lung, And Blood Institute
Abstract: The primary cause of illness and death in patients with cystic fibrosis (CF) is progressive lung disease. CF is caused by a mutation in a chloride channel gene. Defective clearance of airway mucus related to the underlying chloride channel abnormality predisposes patients with CF to chronic airway infection and inflammation which in turn causes progressive airway damage. It is now well established that CF lung disease begins in infancy, frequently prior to the onset of symptoms, providing a rationale for early intervention. Inhaled hypertonic saline (HS) has been shown in short-term studies to improve mucociliary clearance and in long term studies to improve lung function, decrease the rate of pulmonary exacerbations and improve quality of life in CF patients over 6 years of age. There are no efficacy data in younger CF patients. HS is a particularly attractive agent to study in infants because it improves defective mucociliary clearance, an early step in the cascade of events leading to CF lung disease that is expected to be abnormal prior to the onset of airway infection and inflammation. This proposal is for a randomized, controlled trial to assess the efficacy and safety of 7% HS inhaled twice daily for 48 weeks among infants with CF 4 to 15 months of age at enrollment. Our primary hypothesis is that, compared to the control agent (isotonic saline), HS will improve hyperinflation and obstructive lung disease as measured by infant lung function testing. The efficacy and safety results generated by the proposed trial may for the first time provide evidence for early initiation of a therapy used widely in older CF patients, thereby potentially delaying or preventing devastating airway damage before it becomes irreversible. One hundred and fifty infants ages 4 to 15 months will be enrolled at 16 centers. Study visits will take place at enrollment and weeks 4, 12, 24, 36 and 48, generally in conjunction with routine CF clinic visits. Subjects will undergo lung function testing at enrollment, 24 and 48 weeks. The primary endpoint is the change in the functional residual capacity, a measure of hyperinflation, from baseline to end of treatment. Additional lung function measures will also be assessed. The secondary endpoint is the time to first pulmonary exacerbation requiring antibiotic therapy. Other clinical endpoints will include changes in weight and height, resting respiratory rate and oximetry, a standardized cough score, and symptoms by parental home report. Safety will be assessed by evaluation of rates of adverse events, withdrawal, adherence to treatment, new isolation of CF pathogens from respiratory cultures; and clinical parameters measured at study visits during the 48-week treatment period. This Clinical Coordinating Center application is submitted in conjunction with a Data Coordinating Center application. This is the lead application. The public health impact of this study could be significant, as it may provide the first efficacy and long term safety data on hypertonic saline in infants with CF, potentially allowing the use of this promising agent in the youngest CF patients. HS is a particularly attractive agent to study in infants because it improves defective mucociliary clearance, an early step in the cascade of events leading to CF lung disease that is expected to be abnormal prior to the onset of airway infection and inflammation. This would be the first multicenter clinical trial of a pulmonary maintenance therapy specifically in infants with CF, and the first to use measures of infant lung function as an endpoint
Keywords: 6 year old; Adherence (attribute); Adverse event; Age; Age-Months; Air; Antibiotic Therapy; Antibiotics; Breathing; Cessation of life; Child; Chloride Channels; Chronic; Clinic Visits; Clinical; clinical effect; clinical efficacy; Clinical Trials; Conduct Clinical Trials; control trial; Coughing; Cystic Fibrosis; cystic fibrosis patients; Data; Data Coordinating Center; Devices; Dose; Early treatment; Enrollment; Evaluation; Event; Forced expiratory volume function; Functional Residual Capacity; Genes; Height; Home environment; improved; indexing; infancy; Infant; Infection; Inflammation; Inflammatory Response; Intravenous; Isotonic Exercise; Lead; Link; Longitudinal Studies; Lung; Lung diseases; Maintenance Therapy; Measurement; Measures; Morbidity - disease rate; Mortality Vital Statistics; Mucociliary Clearance; Mucous body substance; Multicenter Studies; Mutation; Obstructive Lung Diseases; Oral; Outcome Measure; Oxygen; Oxygen saturation measurement; pathogen; Patients; Physiological; Plethysmography; prevent; Protocols documentation; Pseudomonas aeruginosa; public health medicine (field); Pulmonary Cystic Fibrosis; Pulmonary function tests; Quality of life; Randomized; Randomized Controlled Trials; Reporting; Research Personnel; Residual volume; respiratory; Respiratory physiology; Rest; Safety; Saline; Sedation procedure; Symptoms; Testing; Therapy Clinical Trials; Time; Total Lung Capacity; treatment duration; Visit; Vital capacity; Weight; Withdrawal
Project start date: 2008-09-15
Project end date: 2012-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
PFA/PA: PAR-07-373
5U01HL092932-04 (2011): $184893
COGNITIVE NEURAL PROSTHETICS FOR CLINICAL APPLICATIONS
A Richard
California Institute Of Technologycity: Pasadena country: United States (us)
Grant 5R01EY015545-07 from National Eye Institute
Abstract: The objective of this application is to assess, in human posterior parietal cortex (PPC), the efficacy of both microwire-based array technology and decoding algorithms for neural prosthetic applications. An outcome of this work is a human-approved microwire array technology capable of reaching deep sulcal areas of the cortex. In animals, the posterior parietal cortex is an area that we have shown to encode both the reach target (goal) location and real time dynamics in point-to-point arm reaching tasks. It is our intention to show that, in the human, these features are also encoded and that goal and dynamic information can be combined for more accurate decoding of movement intentions. In addition, our research with animals has demonstrated that the PPC encodes a number of cognitive variables that could be potentially useful for neural prosthetic applications. Tasks will be designed to see if these cognitive signals can also be recorded and decoded from human PPC. These tasks will examine 1) rapid decoding of movement sequences; 2) decoding higher level aspects of goal information that are symbolic and non-spatial; 3) local field potentials to increase decode accuracy and provide a foundation for cognitive state decoding; 4) context decoding; 5) learning as a function of practice for goal and trajectory decoding and 6) learning novel effecter dynamics. We hypothesize that these cognitive aspects of animals´ PPC are also available in the corresponding human PPC. Our five year goal for this grant is to complete the preclinical testing for an investigational device exemption (IDE) to the Food and Drug Administration, submit and gain approval for an IDE, obtain IRB approvals and design the behavioral tasks and data analysis that will be used in subsequent human clinical studies, and perform a clinical trial with two subjects. To this end, we have put forth five specific aims (1) to perform a biocompatibility assessment of the technology per recommended standards, (2) to perform a histological assessment of the technology following chronic implantation, (3) to perform a safety and efficacy assessment in a non-human primate model, (4) to test the performance of decoding algorithms that will be used in humans, and (5) to assess the performance of our technology and cognitive decoding algorithms in paralyzed individuals under an FDA approved Investigational Device Exemption Clinical Trial. This application has direct relevance to public health since its goal is to perform clinical trials to test a neuroprosthetic medical device for implantation in posterior parietal cortex. The clinical trials are designed to help patients with severe paralysis, which can result from spinal cord lesion and other traumatic accidents, peripheral neuropathies, amyotrophic lateral sclerosis, multiple sclerosis, and stroke
Keywords: Accidents; Adverse event; Algorithms; Amyotrophic Lateral Sclerosis; Animals; Area; arm; base; Behavioral; Biocompatible; biomaterial compatibility; Brain; Chronic; Clinic; clinical application; Clinical Research; Clinical Trials; Clinical Trials Design; Cognitive; cognitive control; Collaborations; Computer Interface; Computers; Data; Data Analyses; design; Devices; Disabled Persons; efficacy testing; Elements; Environment; Evaluation; Foundations; gaze; Goals; good laboratory practice; Grant; Health; Homologous Gene; Human; human subject; Implant; implant material; implantation; improved; Individual; Infection; Institutional Review Boards; Intention; Laboratories; Learning; Limb structure; Location; Medical Device; mind control; Modeling; Monitor; Monkeys; Motor Cortex; Movement; Multiple Sclerosis; neural prosthesis; Neurons; nonhuman primate; novel; Outcome; Paralysed; Parietal; Parietal Lobe; Patients; Performance; performance tests; Peripheral Nervous System Diseases; Phase; Phase I Clinical Trials; Positioning Attribute; Preclinical Testing; Process; public health medicine (field); public health relevance; relating to nervous system; Research; research study; response; Robotics; Rodent Model; Safety; Series; Signal Transduction; Site; Skin; Source; Spinal Cord Lesions; stroke; Technology; Technology Assessment; Testing; Time; United States Food and Drug Administration; Utah; virtual reality; Work; wound
Relevance: Relevance to Public Health This application has direct relevance to public health since its goal is to perform clinical trials to test a neuroprosthetic medical device for implantation in posterior parietal cortex. The clinical trials are designed to help patients with severe paralysis, which can result from spinal cord lesion and other traumatic accidents, peripheral neuropathies, amyotrophic lateral sclerosis, multiple sclerosis, and stroke
Project start date: 2004-04-01
Project end date: 2013-08-31
Budget start date: 1-SEP-2011
Budget end date: 31-AUG-2012
PFA/PA: PA-07-070
5R01EY015545-07 (2011): $489040
2R01EY015545-06 (2010): $568989
LABORATORY FOR ANTI-GERIC TESTING, EVALUATION AND RESEARCH
A Richard, Professor
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Grant 5U01AG022303-08 from National Institute On Aging
Abstract: The NIA Interventions Testing Program represents a multi-site translational research program to evaluate agents hypothesized to extend mouse lifespan by retardation of aging or postponement of late life diseases. Interventions proposed by multiple collaborating scientists from the research community are initially tested, in parallel, at three sites (Jackson Laboratories, Michigan and Texas), using identical, standardized protocols, and using sufficient numbers of genetically heterogeneous mice to provide 80% power for detecting changes in lifespan of 10%, for either sex, after pooling data from any two of the test sites. Eighteen such ´Phase I´ trials have been started in the first four years of the ITP, with 4-5 new agents tested in each annual cycle. Two agents tested in the first annual mouse cohort, aspirin and NDGA, produced significant increases in survival of male mice. Rapamycin, given to mice at 20 months of age and then evaluated at a point (Dec 1, 2008) where 92% of 867 female mice, and 96% of 1098 male mice from Cohort 2 had died, produced robust lifespan increases with p < 0.0001 for males and p < 0.0001 for females, with significant parallel results at all three sites. Rapamycin treatment also led to a significant increase in maximum lifespan both in males and in females (p < 0.001 in each sex). Rapamycin also shows a beneficial effect when initiated at 9 months of age, in a Cohort 3 study now reaching the median survival age, significant in both male (p = 0.008) and female (p = 0.0001) mice. Plans for the next five years include completion of all ongoing Phase I trials and initiation of three or more new Phase I trials each year. In addition, a more elaborate Phase II study of Rapamycin will evaluate the effects of varying doses of this agent on survival, test a range of age-sensitive traits and proposed mechanistic pathways, document cross-sectional pathology, and provide mice and tissues for analyses by others. Each of the three laboratories has experience in lifespan and biomarker analysis in mice, and in addition will bring special expertise to the collaboration measures of age-sensitive traits at the Jackson Laboratory, pathology and statistical analysis at Michigan, and pharmacology/toxicology at Texas. RELEVANCE Identification of agents that can extend mean and/or maximum longevity in genetically heterogeneous mice in multiple laboratories will suggest research directions leading to clinical treatments designed to prevent or retard deleterious changes with age. In addition, identifying health dangers of unproven treatments that are purported to have anti-aging actions will also have public health benefits
Keywords: Adrenal Glands; Age; age related; Age-Months; Aging; Animals; anti aging; Aspirin; base; Behavioral; Biochemical; Biology of Aging; biomarker; Blood Urea Nitrogen; Body Composition; Clinical Treatment; Cognition; cohort; Collaborations; Communities; Creatinine clearance measurement; Data; design; Development; DEXA; Disease; DNA Damage; Dose; Elderly; Evaluation; Evaluation Research; experience; feeding; Female; follow-up; Genome Stability; Glycosylated Hemoglobin; Health; Health Benefit; Health Sciences; Heart; Hematopoietic stem cells; Human; human FRAP1 protein; insight; insulin sensitivity; Insulin-Like Growth Factor I; Intervention; isoprostaglandin F2alpha type-III; Kidney; Laboratories; Lead; Link; Liver; Longevity; Lung; male; Mammals; Measures; Meta-Analysis; Metabolic; Methods; Michigan; Mortality Vital Statistics; Mus; New Agents; Nordihydroguaiaretic Acid; Outcome; Pancreas; Pathology; Pathway interactions; Pharmacology and Toxicology; Phase; phase 1 study; phase 2 study; Phase I Clinical Trials; Phase II Clinical Trials; Physiological; Pilot Projects; prevent; programs; Proteins; Protocols documentation; public health medicine (field); Reporting; Research; research study; respiratory; Risk; Route; Scientist; Series; sex; Signal Transduction; Sirolimus; Site; Skeletal muscle structure; System; Testing; Texas; The Jackson Laboratory; therapy design; Tissues; trait; Translational Research; Universities; Work
Project start date: 2003-07-01
Project end date: 2014-06-30
Budget start date: 1-AUG-2011
Budget end date: 30-JUN-2012
PFA/PA: RFA-AG-09-013
5U01AG022303-08 (2011): $634160
RHOGTPASES IN EARLY EYE DEVELOPMENT
A Richard, Emma & Irving Goldman Scholar
Children´s Hospital Med Ctr (cincinnati)city: Cincinnati country: United States (us)
Grant 5R01EY017848-05 from National Eye Institute
Abstract: The long-term goal of this application is an understanding of the mechanisms of early eye development. More specifically, we wish to understand how actin-modulating GTPases influence the coordinated morphogenesis of the lens and retinal epithelium. The Rho family GTPases that are the focus of this application act as molecular switches that regulate signaling within the cell. They function in many different capacities, but have a prominent role in the regulation of actin rearrangement and consequently, the regulation of cell shape, cell migration and the generation of cellular protrusions. They can also influence cell survival. We outline 4 aims to investigate their function in early eye morphogenesis (1) To determine whether Cdc42 and Rac1 function in a cascade to regulate lens vesicle closure and separation, (2) To determine whether early deletion of Cdc42, Rac1 or RhoA gives a defect in lens pit invagination, (3) To determine whether the optic vesicle has a dominant role in lens pit invagination, and (4) To determine whether the FGF signaling pathway modulates activity of the Rac1, Cdc42 or RhoA pathways. This application has direct significance to human health because the Rho family GTPases are implicated in a variety of human disease including cancer. The involvement of the GTPases in the etiology of cancer is derived from their ability to regulate cell adhesion, cell migration and cell survival. The process of epithelial invagination that we will study is in many ways analogous to the process of invasion that accompanies the development of aggressive cancers. For this reasop, this project may have implications for cancer therapy
Keywords: Abbreviations; Actins; Alleles; Apical; base; Behavior; biological systems; Biology; Budgets; Cancer Etiology; cancer therapy; cell motility; Cell Shape; Cell Survival; Cell-Cell Adhesion; Cells; Characteristics; Defect; design; Development; DNA Sequence Rearrangement; Ectoderm; Epithelial; Epithelium; Equilibrium; experience; Eye; Eye Development; Failure (biologic function); Family; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Funding; Generations; Genes; Genetic; Genetic Techniques; Goals; Grant; GTPase-Activating Proteins; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Health; Human; human disease; Immunofluorescence Immunologic; innovation; Investigation; laser capture microdissection; lens; lens morphogenesis; Lens Pit; Literature; loss of function; Malignant Neoplasms; Messenger RNA; Molecular; Monomeric GTP-Binding Proteins; Morphogenesis; Movement; Mus; Names; Nomenclature; Optic vesicle; Outcome; Pathway interactions; Phenotype; Polymerase Chain Reaction; Process; Production; programs; Proteins; recombinase; Regulation; Regulation of Cell Shape; Research Personnel; Retina; Retinal; rho; rho GTP-Binding Proteins; Role; Signal Pathway; Signal Transduction; Surface Ectoderm; System; Testing; Text; Time; Tissues; tool; tumor; Vesicle; Work
Project start date: 2007-04-06
Project end date: 2012-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
5R01EY017848-05 (2011): $300713
THEORETICAL STUDIES OF METALLOPROTEIN CHROMOPHORES
A Richard, Pi
Columbia Univ New York Morningsidecity: New York country: United States (us)
Grant 5R01GM040526-23 from National Institute Of General Medical Sciences
Abstract: The long term goal of this project is the development of computational methods that will enable accurate modeling of protein active site chemistry at an atomic level of detail, with a primary focus on metalloproteins. Such modeling will provide insight into biological functioning of metalloenzymes and transport proteins, and facilitate the design of pharmaceutically relevant compounds interacting with these systems. The computational methods that we are developing include new approaches to density functional theory, mixed quantum mechanics/molecular mechanics methods, sampling algorithms for treating protein conformational transitions, and algorithms to calculate overall free energy changes for chemical reactions of interest. Specific proteins to be studied in the proposed granting period include methane mono-oxygenase, cytochrome P450, and hemoglobin. Cytochrome P450, which plays a fundamental role in drug metabolism, will be a particular focus of the project. We will continue to work on understanding the fundamental mechanism of hydroxylation, but at the same time, building on promising preliminary results obtained over the past several years, will investigate the conformational plasticity of the active site which is a critical aspect of the ability of these enzymes to interact with a wide variety of compounds. A direct, health related goal of the project is to develop a suite of tools for creating a reliable structural and energetic model of pharmaceutically relevant compounds interacting with human P450 isoforms; such a model would be immediately useful the late stages of lead optimization to modify preclinical candidates which exhibit problems with P450 metabolism
Keywords: Academia; Active Sites; Address; Affinity; Algorithms; Area; base; Biochemical Reaction; Biological; Biological Models; Biological Process; biological systems; Biotechnology; Carrier Proteins; chemical reaction; Chemistry; chromophore; Collaborations; Computer Simulation; Computer software; Computing Methodologies; conformational conversion; Cytochrome P450; density; design; Development; Docking; Drug Design; drug metabolism; Effectiveness; electronic structure; Electrons; energy density; Enzymes; Event; Exhibits; Free Energy; Freedom; Goals; Grant; graphical user interface; Health; Hemoglobin; Human; Hydroxylation; Industry; insight; interest; ionization; knowledge base; Laboratories; Lead; Ligands; Measurement; Metabolic; Metabolic Pathway; Metabolism; metalloenzyme; Metalloproteins; Methane; Methane hydroxylase; method development; Methodology; Methods; Modeling; Molecular; molecular mechanics; Mono-S; Myoglobin; novel; novel strategies; Oxygenases; Panthera onca; Pharmacologic Substance; Physical Chemistry; Play; Potential Energy; pre-clinical; programs; Progress Reports; Property; Protein Isoforms; protein structure; Proteins; quantum chemistry; Quantum Mechanics; Reaction; Relative (related person); Research; research study; Resolution; Role; Sampling; Screening procedure; Staging; Structural Models; Surface; System; Technology; Theoretical model; Theoretical Studies; theories; Time; tool; Transition Elements; Triose-Phosphate Isomerase; user friendly software; Work
Project start date: 1988-07-01
Project end date: 2012-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-07-070
5R01GM040526-23 (2011): $270710
INFLUENCE OF PERSONAL RESPONSIBILITY RHETORIC ON PUBLIC HEALTH OUTCOMES IN JUDICI
A Richard, Professor Of Law
Northeastern Universitycity: Boston country: United States (us)
Grant 5R01CA087571-07 from National Cancer Institute
Abstract: The investigators propose to examine the tobacco, fast food and sweetened beverage industries´ use of personal responsibility rhetoric in legal and regulatory forums where many public health policies, both positive and negative, are created. As a response to legal context, the tobacco industry invokes personal responsibility rhetoric to focus attention away from its conduct and toward the individual in responding to the harm. When used as the basis of legislative and regulatory oversight, in judicial proceedings, or in other forums of law and policy formation, the concept of personal responsibility exploited rhetorically to obscure or shift attention from larger structural determinants -- including culpable actors -- that adversely affect the public´s health. The investigators will identify the judicial, regulatory, legislative operational processes and related media coverage that have facilitated the use of personal responsibility rhetoric by the tobacco industry and those processes that have resisted such rhetoric in favor of analyses of structural determinants of health behaviors. The tobacco industry´s personal responsibility rhetoric may also serve as a model for other commercial interests faced with the recognition that their products are harming the public´s health. The investigators will examine rhetoric in the judicial, regulatory, legislative forums and related media by the fast food and sweetened beverage industries in their identified role in the obesity epidemic and compare their rhetoric with that deployed by the tobacco industry. Research will be oriented around nine key law and policy events, which will function as the investigators´ theoretical samples. The theory is that the use of personal responsibility rhetoric shields from scrutiny in the judicial, regulatory and legislative forums commercially engineered determinants of health behavior. In addition to traditional law and policy research, the investigators rely on ethnographic content analysis to examine datasets containing internal industry tobacco documents, legal documents generated in the relevant legal forums, news media coverage, industry public relations documents and other documentation of conduct by the tobacco, fast food and sweetened beverage industries. The investigators will develop an initial coding scheme based on a preliminary literature reviews and examination of samples of text in the identified datasets. The investigators will test the coding on samples from the identified datasets. The study findings will be described in articles to be published in peer-reviewed publications and actively disseminated through participation in scholarly forums. By understanding the tobacco industry´s rhetorical use of the concept of personal responsibility in legal and regulatory forums such as courts and legislatures where much health policy is determined, and analyzing how this rhetoric appears in news, opinion and public relations media material, it will be possible to more effectively anticipate and counter such rhetoric and enact evidence-based public health interventions in legal and regulatory forums. Extending the analysis of the use of such rhetoric to the "fast food" and sweetened beverage industries that are implicated in the obesity epidemic and comparing these approaches to that of the tobacco industry will better prepare policy-makers for undertaking important policy interventions to reduce obesity and its escalating public health impact
Keywords: adiposity; Advertising; Affect; Amendment; Attention; base; Behavior; California; Cigarette; Code; Coding System; Concept Formation; conceptual processes; Consumption; convenience food; corpulence; corpulency; corpulentia; court; Data Set; Dataset; Documentation; Engineering; Engineerings; Epidemic; ethnographic; Ethnography; Event; evidence base; failure; Failure (biologic function); fast food; FLR; Food; Food Industry; Fostering; Fraud; Health; Health behavior; health care policy; Health Policy; Individual; Industry; Injury; interest; Intervention; Intervention Strategies; interventional strategy; Investigation; Investigators; Label; Laws; Legal; Light; Litigation; Marketing; Massachusetts; Medicaid; Methodology, Research; Modeling; New Hampshire; New York City; news; News; News (PT); News [Publication Type]; Nicotine; Nutritional; obese; obese people; obese person; obese population; Obesity; Outcome; Peer Review; Photoradiation; Policies; Policy Maker; Policy Making; Policy Research; Process; Public Health; public health medicine (field); public policy on tobacco; Public Relations; Publications; Publishing; Pyridine, 3-(1-methyl-2-pyrrolidinyl)-, (S)-; Research; Research Design; Research Methodology; Research Methods; Research Personnel; Researchers; response; Restaurants; Review Literature; Role; Rosa; Rose; Sampling; Scheme; Scientific Publication; Smoking; social role; Societies; study design; Study Type; sweetened beverage; Testing; Text; theories; Tobacco; tobacco ads; tobacco advertising; tobacco control; tobacco control policy; Tobacco Industry; tobacco policy; Trans Fats; TXT
Relevance: By understanding the tobacco industry´s rhetorical use of the concept of personal responsibility in legal and regulatory forums such as courts and legislatures where much health policy is determined, and analyzing how this rhetoric appears in news, opinion and public relations media material, it will be possible to more effectively anticipate and counter such rhetoric and enact evidence-based public health interventions in legal and regulatory forums. Extending the analysis of the use of such rhetoric to the "fast food" and sweetened beverage industries that are implicated in the obesity epidemic and comparing these approaches to that of the tobacco industry will better prepare policy- makers for undertaking important policy interventions to reduce obesity and its escalating public health impact
Project start date: 2000-09-01
Project end date: 2014-02-28
Budget start date: 1-MAR-2011
Budget end date: 29-FEB-2012
PFA/PA: PA-07-070
5R01CA087571-07 (2011): $466286
A Richard, Professor
Mayo Cliniccity: Rochester country: United States (us)
Grant 5U01HL089645-03 from National Heart, Lung, And Blood Institute
Abstract: The investigator-initiated, Catheter Ablation Versus Anti-arrhythmic Drug Therapy for Atrial Fibrillation (CABANA) Trial will test the hypothesis that the treatment strategy of percutaneous left atrial catheter ablation for the purpose of eliminating atrial fibrillation (AF) is superior to current state-of-the-art pharmacologic therapy with either rate control or rhythm control drugs for reducing total mortality (primary endpoint) and decreasing the composite endpoint of total mortality, disabling stroke, serious bleeding and cardiac arrest (secondary endpoint) in patients with untreated or incompletely treated AF warranting therapy. Additional secondary endpoints will include AF recurrence and quality of life and cost effectiveness. The need for this trial arises out of 1) the rapidly increasing number of patients >60 years of age with AF accompanied by symptoms and morbidity, 2) the failure of anti-arrhythmic drug therapy in multiple recent trials to maintain sinus rhythm and reduce mortality, 3) the rapidly increasing application of radiofrequency catheter ablation for AF without appropriate evidence-based validation, and 4) the resulting impact of AF on national health care costs. This 140-center mortality study will randomize 3000 patients over 3 years to a strategy of catheter ablation (n=1500) vs. state-of-the-art rate or rhythm control drug therapy (n=1500). Each patient will have 1) characteristics similar to AFFIRM patients (age >65, or <65 with >1 risk factor for stroke, 2) documented AF warranting treatment, and 3) eligibility for both catheter ablation and >2 anti-arrhythmic or >3 rate control drugs. Patients will be followed every 6 months for >2 yrs (median 3.5 yrs) and will undergo repeat trans-telephonic monitoring, Holter monitoring, and CT/MR studies to assess the impact of treatment. The primary and secondary endpoints will be examined in pts with paroxysmal, persistent, or permanent AF, without regard to age or underlying heart disease. With an anticipated 3.5 year mortality rate of >12% in drug treated patients, 1500 patients in each treatment arm will provide 90% power for detecting a 30% relative reduction in overall mortality and >90% power for detecting a 25% reduction in the composite secondary endpoint. The CABANA trial will disclose the role of medical and ablative therapies for an ever-escalating national healthcare dilemma, ascertain the cost and influence of therapy on quality of life, establish the impact of therapy on atrial morphology and function, and will help determine if AF is a modifiable risk factor for cardiovascular mortality. CABANA will be a landmark trial that will guide therapy and shape health care policy in the AF arena for years to come
Keywords: Ablation; Accessory Sinuses; After Care; After-Treatment; Aftercare; Age; Age-Years; aging population; Algorithms; Anti-Arrhythmia Agents; Anti-Arrhythmia Drugs; Anti-Arrhythmics; Antiarrhythmia Agents; Antiarrhythmia Drugs; antiarrhythmic agent; Antiarrhythmic Drugs; Apoplexy; arm; Arrhythmia; arrhythmic agent; Asystole; Atrial; Atrial Fibrillation; Atrial Function; atrium; Atrium, Left; Auricle of Heart; Auricular Fibrillation; base; Bleeding; blood loss; Body Tissues; brain attack; Caliber; Cardiac ablation; Cardiac Arrest; Cardiac Arrhythmia; Cardiac Atrium; Cardiac Diseases; Cardiac Disorders; Cardiac Surgery; Cardiac Surgery procedures; Cardiac Surgical Procedures; Cardiovascular; Cardiovascular Body System; Cardiovascular system; Cardiovascular system (all sites); Care, Health; Catheter Ablation; Catheters; Cerebral Stroke; cerebral vascular accident; Cerebrovascular accident; Cerebrovascular Apoplexy; Cerebrovascular Stroke; Characteristics; Chest; Cicatrix; circulatory system; clinical investigation; Clinical Trials; Clinical Trials, Unspecified; Communication; computer program/software; Computer Programs; Computer software; Constriction, Pathologic; Constriction, Pathological; cost; cost effectiveness; Data Coordinating Center; Data Coordination Center; Diameter; Drug Controls; Drug Therapy; drug/agent; Drugs; Dysfunction; EFRAC; Ejection Fraction; ELIG; Eligibility; Eligibility Determination; Esophageal injury; Esophagus; evidence base; failure; Failure (biologic function); FLR; Functional disorder; Gastrointestinal Tract, Esophagus; Goals; graphic user interface; Graphical interface; graphical user interface; Health Care Costs; health care policy; Health Costs; Health Policy; Healthcare; Healthcare Costs; Heart Arrest; Heart Arrhythmias; Heart Atrium; Heart Diseases; heart disorder; heart surgery; Hemorrhage; Holter Electrocardiography; Holtmon; Image; Image Analyses; Image Analysis; image evaluation; imaging; improved; Incidence; Injury to Esophagus; insight; interest; Investigation; Investigators; Left; Left atrial structure; Left Atrium of Heart; Link; Living Costs; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Measurement; Measures; Medical; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Medication; Methods; Methods and Techniques; Methods, Other; minimally invasive; modifiable risk; Monitor; Monitoring, Holter; Morbidity; Morbidity - disease rate; Morphology; Mortality; Mortality Vital Statistics; MR Imaging; MR Tomography; MRI; Myocardial; Nasal cavity/Paranasal; Nasal cavity/Paranasal sinuses; Nasal Sinuses; NMR Imaging; NMR Tomography; Nuclear Magnetic Resonance Imaging; Operation; Operative Procedures; Operative Surgical Procedures; Organ System, Cardiovascular; Outcome; Pace Stimulators; Pacemakers; Paranasal Sinuses; pathophysiology; Patients; Performance; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Preparations; Pharmaceuticals; Pharmacologic Substance; Pharmacological Substance; Pharmacotherapy; Phase; Physiopathology; Prevalence; Process; Protocol; Protocol Screening; Protocols documentation; Public Health; public health medicine (field); Pulmonary veins; QOL; Quality of life; Radiofrequency Catheter Ablation; randomisation; randomization; Randomized; randomly assigned; Recurrence; Recurrent; Relative; Relative (related person); Reporting; Research Personnel; Researchers; response; Risk; Risk Factors; ROC Analysis; Role; Scanning; Scars; Shapes; Sinus; social role; Software; Stenosis; Stimulators, Electrical, Pace; stroke; Stroke; Structure; surgery; Surgical; Surgical Interventions; Surgical Procedure; Surgical Procedures, Heart; Symptoms; System; System, LOINC Axis 4; Techniques; Testing; Thorace; Thoracic; Thorax; Tissues; treatment effect; treatment strategy; Validation; Variant; Variation; Vascular Accident, Brain; Vascular, Heart; Zeugmatography
Relevance: The rapidly increasing incidence of cardiac arrhythmias, and particularly atrial fibrillation (AF), in an aging population has become a major public health problem. Current prevalent treatments for atrial fibrillation are medication (pharmaceuticals), pacemakers, catheter-based myocardial ablation, and open chest heart surgery. Pacemakers are ineffective in many patients, especially those with AF, and due to the risk and morbidity of surgery, the potential for effective, less invasive treatments has become of high interest. However, no compelling quantitative comparison of performance and outcomes for pharmaceutical versus ablative treatment has been accomplished. This proposal, one of four linked in a synergistic coalition to conduct a large clinical trial, will provide exactly the quantitative measures required to settle the issue and produce a "winner". That method will become the compelling first choice for effective minimally invasive treatment for millions of people who have serious atrial fibrillation
Project start date: 2009-02-01
Project end date: 2015-01-31
Budget start date: 1-FEB-2011
Budget end date: 31-JAN-2012
PFA/PA: PA-07-070
5U01HL089645-03 (2011): $264425
RESISTANCE TRAINING ENERGY BALANCE AND WEIGHT MANAGEMENT
A Richard, Research Associate
University Of Kansas Lawrencecity: Lawrence country: United States (us)
Grant 5R01DK080832-03 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: The increased prevalence of obesity and the lack of treatment success both argue for the design and evaluation of strategies to prevent the development of overweight and obesity. To date, the role of resistance training (RT) in the prevention of overweight and obesity is largely unexplored. RT may have a positive impact on weight management and health as a result of increased fat-free mass (FFM), which may result in increased resting metabolic rate and increased physical activity energy expenditure (i.e., increased total daily energy expenditure). However, the literature relative to the efficacy of RT protocols recommended for healthy adults to alter the aforementioned parameters is inconsistent or inadequately evaluated. We have recently completed a 6 month pilot randomized controlled trial (DK62832) in overweight young adults which evaluated the effect of a supervised minimal RT protocol (3 days/wk, 1 set, 3-6 repetitions maximum, 9 exercises, 11 minutes to complete) on body composition (DEXA), resting and sleeping metabolic rate (whole-room calorimeter). In general, our pilot results suggested a positive impact of RT on body composition and energy expenditure. Based on these results, we propose to conduct a randomized controlled efficacy trial (RT-1 set vs. RT-3 sets vs. non exercise control) to evaluate the potential for a longer intervention (9 months RT with body composition assessments 1 yr post RT completion) with a higher volume of RT (3 sets) to enhance the effects on body composition and energy expenditure observed in the pilot, and to determine the impact of the 2 levels of RT on free-living energy balance (expenditure by doubly labeled water and intake by digital photography and 24-hr recalls). This investigation will be conducted in a sample of healthy, normal and overweight, sedentary, young adult men and women; a group at high risk for development of overweight and obesity. The specific aims of this project are to determine the impact of the volume (1 vs. 3 sets) of a progressive RT protocol for inducing muscular hypertrophy, as recommended by the American College of Sports Medicine, on body weight and body composition (fat mass, FFM, percent body fat) and energy balance. Our results will provide information relative to the minimum volume of RT that may be associated with body weight/fat gain which may inform the development of guidelines for RT to prevent weight gain or to alter body composition. If RT has a favorable impact on energy balance and body composition, it may provide an attractive alternative to aerobic exercise for weight management for busy young adults, as RT requires minimal time, and no need to change clothes or shower (i.e. minimal or no sweating). The specific aims of this project are to determine the impact of the volume (1 vs. 3 sets) of a progressive resistance training protocol for inducing muscular hypertrophy, as recommended by the American College of Sports Medicine, on body weight and body composition (fat and lean mass), and the balance between energy intake and energy expenditure. Our results will provide information relative to the minimum volume of resistance training that may be associated with body weight/fat gain which may inform the development of guidelines for resistance training to prevent weight gain or to alter body composition. If resistance training has a favorable impact on energy balance and body composition, it may provide an attractive alternative to aerobic exercise for weight management for busy young adults, as resistance training requires minimal time, and no need to change clothes or shower (i.e. minimal or no sweating)
Keywords: Adult; Aerobic Exercise; American; Basal metabolic rate; base; Body Composition; Body fat; Body Weight; Cardiovascular Diseases; Centers for Disease Control and Prevention (U.S.); Chronic Disease; Clothing; college; Comorbidity; design; Development; DEXA; Diabetes Mellitus; Digital Photography; Dose; efficacy trial; energy balance; Energy Intake; Energy Metabolism; Equilibrium; Evaluation; Exercise; Expenditure; Fatty acid glycerol esters; fitness; Gender; Guidelines; Health; Health Professional; high risk; Hypertension; Hypertrophy; Individual; Intervention; Investigation; Label; Life; Literature; Malignant Neoplasms; men; Metabolic; Modeling; Muscle; Obesity; obesity treatment; Overweight; oxidation; Physical activity; Prevalence; prevent; Prevention; programs; Protocols documentation; Randomized; Randomized Controlled Trials; Relative (related person); Reporting; Resistance; response; Rest; Role; Sampling; sedentary; Sleep; Sports Medicine; strength training; success; Surgeon; Sweat; Sweating; Time; Training; trend; Water consumption; Weight; Weight Gain; Woman; young adult
Relevance: Relevance The specific aims of this project are to determine the impact of the volume (1 vs. 3 sets) of a progressive resistance training protocol for inducing muscular hypertrophy, as recommended by the American College of Sports Medicine, on body weight and body composition (fat and lean mass), and the balance between energy intake and energy expenditure. Our results will provide information relative to the minimum volume of resistance training that may be associated with body weight/fat gain which may inform the development of guidelines for resistance training to prevent weight gain or to alter body composition. If resistance training has a favorable impact on energy balance and body composition, it may provide an attractive alternative to aerobic exercise for weight management for busy young adults, as resistance training requires minimal time, and no need to change clothes or shower (i.e. minimal or no sweating)
Project start date: 2009-04-01
Project end date: 2013-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-07-070
5R01DK080832-03 (2011): $367082
Sponsored Links Excellgen http://Excellgen.com
DEVELOPMENT OF NOVEL BROAD SPECTRUM CHEMOTHERAPEUTICS AGAINST PRIORITY PATHOGENS
A Richard, Assistant Professor
Colorado State University-fort Collinscity: Fort Collins country: United States (us)
Abstract: The hypothesis of this program is that Fabl, the conserved enoyl reductase enzyme in the bacterial fatty acid biosynthesis pathway, is a target for the development of preclinical lead compounds with broad spectrum activity against priority pathogens, including F. tularensis, B. pseudomallei, and Y. pestis. Based on this approach, we have developed inhibitors with potent activity against the Fabl enzyme from F. tularensis and 8. pseudomallei. Significantly, we have demonstrated efficacy in an animal model of tularemia. Encouraged by this progress and due to the need to develop chemotherapeutics against other priority pathogens, we will extend our studies to include the development of potent in vivo antibacterial agents against 6. pseudomallei and Y. pestis. Our overall goal is to rapidly progress lead compounds into animal models of infection for efficacy testing with the following Specific Aims Aim 1 Rational Optimization of Lead Compounds Against F. tularensis. We will design and synthesize subsequent generations of our lead compounds using SAR information derived from molecular modeling, activity against whole bacteria and efficacy in animals and bioavailability studies. Aim 2 In Vitro and In Vivo Antibacterial Activity against B. pseudomallei. The in vitro activity of the current diphenyl ether compounds against 8. pseudomallei will be assessed by determining (i) the IC50 for inhibition of the 8. pseudomallei Fabl enzyme (FablBpm), (ii) antibacterial activity (MIC and MBC) (iii) toxicity, PK/PD and deliverability. Selected compounds will be progressed to efficacy testing in the 8. pseudomallei animal model of infection. Aim 3 Extension to Y. pestis. We will extend our antibacterial discovery efforts to include the pathogen Y. pestis. Testing will be conducted using the established approach and compounds with appropriate activity will be evaluated in animal models of infection. This research project fits within the RMRCE Integrated Research Focus on Bacterial Therapeutics, and will interact directly with RP 2.1, RP 2.2, RP 2.5 and RP 2.6, and utilize the resources of Core C and Core E
Keywords: Acinetobacter baumannii; Affinity; Animal Model; Animals; Anti-Bacterial Agents; Bacteria; base; biodefense; Biological Availability; Burkholderia pseudomallei; Chemicals; design; Development; efficacy testing; efflux pump; enoyl reductase; Enzymes; fatty acid biosynthesis; Francisella tularensis; Generations; Goals; Health; improved; In Vitro; in vitro activity; in vivo; Infection; inhibitor/antagonist; Inhibitory Concentration 50; Lead; Melioidosis; methicillin resistant Staphylococcus aureus (organism); molecular modeling; Molecular Models; mutant; novel; pathogen; Pathway interactions; phenyl ether; Plague; pre-clinical; preclinical study; programs; Property; Pseudomonas aeruginosa; Research; Research Project Grants; Resources; Series; Testing; Therapeutic; TNFRSF5 gene; Toxic effect; Tularemia; Yersinia pestis
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
5U54AI065357-07_6132 (2011): $348679
A Richard, Assistant Professor
Colorado State University-fort Collinscity: Fort Collins country: United States (us)
Abstract: The goal of the Genomics Proteomics Core (Core E) of the Rocky Mountain Regional Center of Excellence in Biodefense (RMRCE) is to provide post-genomic resources and materials, to provide access to state-ofthe- art post-genomic instrumentation, and to provide expert assistance in performing post-genomic experiments, and bioinformatics, resulting in enhanced research opportunities for investigators at reduced costs. The GP-Core accomplishes this goal by producing whole genome mouse and pathogen DMA arrays and other molecular detection tools and platforms, by providing and maintaining post-genomic instrumentation in a centralized facility adjacent to the BL-3 laboratories, and by performing experimentation for investigators who would otherwise not be able to perform experiments because of a lack of manpower or expertise, and providing access to bioinformatics resources, staff, and support. The GP-Core also develops technology and custom platforms for investigators for focused or more advanced post-genomic studies. Accordingly, the GP-Core (1) produces and develops post-genomic resources for investigators, (2) provides access to post-genomic equipment (3) provides genomics, proteomics, and bioinformatics assistance and technical expertise, and (4) provides bioinformatics and Computer-Aided Drug Design (CADD) services to advance diagnostic and therapeutic drug discovery, design, and development for RMRCE investigators. Together, the activities of the GP-Core support research objectives on infectious diseases important to public health by providing resources and equipment that are required for post-genomic studies, technical assistance for experimental design, data analysis and other bioinformatics-related analyses, and postgenomic services on a fee-for-services basis. Core E will support all three of the RMRCE Integrated Research Foci on Immunomodulation, Adjuvants and Vaccines (IRF 1), Bacterial Therapeutics (IRF 2), and Viral Therapeutics (IRF 3). Its resources will be utilized by RPs 1.4, 1.6, 1.7, 2.1, 2.2, 2.3, 2.4, 2.5, 2.7 and 3.4
Keywords: Arts; base; Binding (Molecular Function); biodefense; Bioinformatics; Communicable Diseases; Computer Assisted; computing resources; Core Facility; cost; Custom; Data Analyses; design; Detection; Development; Diagnostic; Drug Design; drug discovery; Equipment; Experimental Designs; Facility Accesses; Fee-for-Service Plans; Genomics; Goals; Human Resources; immunoregulation; instrumentation; Laboratories; Learning; man; Molecular; mouse genome; pathogen; Price; Proteomics; public health medicine (field); Research; Research Personnel; research study; Research Support; Resources; Role; Services; Technical Expertise; Technology; Therapeutic; tool; Vaccine Adjuvant; Viral
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
5U54AI065357-07_6151 (2011): $201453
CELL AND MOLECULAR BIOLOGY CORE
A Richard, Professor
University Of Michigan At Ann Arborcity: Ann Arbor country: United States (us)
Abstract: The goal of the Cell & Molecular Biology (CMB) Core is to enhance and extend the quality and scope of individual research projects, by providing access to molecular technologies and measures that will yield insights into the molecular basis for hearing and hearing impairment. To achieve this goal the CMB Core has Specific Aims that fall into four areas Development, Education, Collaboration and Service. In Development, the CMB will bring new methods and approaches to individual investigators and develop technology and data bases to facilitate use of the mouse model. In Education, the CMB will provide information on new advances in methodology to individual investigators, train staff of individual investigators in both routine and novel molecular methodologies, provide a bridge to centralized University of Michigan facilities for novel and advanced methodologies, and hold monthly meetings of Core Discussion Group with outside experts on specific topics to introduce new methods and approaches, share experiences, problems and successes and develop new productive collaborations. This last goal will be expanded In Collaborations, in which the CMB will bring new investigators to the study of hearing and balance research, bring in outside experts for new directions and approaches, and provide a format for discussions leading to new areas and directions of research. For Service, the CMB will provide state-of-the-art support for morphological and molecular assessments, provide assistance in integration of morphological and molecular assessments, provide normative data bases and provide assistance in experimental design and interpretation of results. The CMB Core will also work closely with the Physiology Core and the Delivery Core to coordinate physiological and morphological characterization of animals at both the molecular and systems level to enhance our understanding of hearing and to define molecular interventions that will prevent and treat hearing loss
Keywords: Address; Animals; Area; auditory pathway; base; Brain; Cells; Cellular biology; clinical application; Collaborations; Consult; Consultations; Data; Data Analyses; Databases; design; Development; Educational aspects; Equilibrium; experience; Experimental Designs; Eye; falls; Gene Delivery; Genes; Goals; Grant; Hearing; hearing impairment; Individual; innovation; innovative technologies; insight; Intervention; investigator training; Laboratories; Labyrinth; Measures; meetings; Methodology; Methods; Michigan; Molecular; Molecular Biology; mouse model; novel; Outcome; Peptides; Pharmaceutical Preparations; Physiological; Physiology; prevent; Productivity; Reagent; Research; Research Institute; Research Personnel; Research Project Grants; research study; Resources; Services; Site; small molecule; success; System; Technology; technology development; Testing; Therapeutic Studies; Training; Universities; Work
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
5P30DC005188-10_9005 (2011): $232710
5P30DC005188-09_9005 (2010): $247352
ALCOHOL DEPENDENCE IN AFRICAN AMERICANS: A CASE-CONTROL GENETIC STUDY
A Richard
Washington Universitycity: Saint Louis country: United States (us)
Grant 5R01AA017444-03 from National Institute On Alcohol Abuse And Alcoholism
Abstract: The global aim of the proposed project is to identify and understand the genetic determinants of alcohol dependence, comorbid nicotine dependence, and other drug dependence in African-Americans. To date, the majority of genetic findings related to addiction have come from samples of primarily European descent. With the large volume of data emerging from genome-wide association studies (GWASs) of alcohol dependence and related disorders, replication and validation across populations will play critical roles in solidifying knowledge about genetic determinants of these disorders. Because these emerging GWASs are largely being conducted primarily in samples of European descent, findings from them will need to be validated across populations. Cross-population validation is a key aspect of the gene-discovery process because allele frequencies differ across ethnic groups. In addition, differences in linkage-disequilibrium patterns between African-American and European-American samples can be used to refine genetic signals initially identified in populations of European descent. Hence, this sample would facilitate the important steps of validation and refinement of genetic findings. The project will ascertain 1,000 cases and 1,000 controls matched on gender, age, zip code, and education, from the African-American community. Cases will consist of subjects seeking treatment for alcohol dependence, either alone, or comorbid with other drug dependence; controls will comprise subjects who have consumed alcohol, but are not dependent on alcohol or other substances. Men and women will be equally represented among both cases and controls, so that maximal power to detect gender specific associations is obtained. Thorough assessment of alcohol dependence, comorbid drug dependence, psychiatric disorders, and risk factors will be carried out with widely-used, diagnostic interviews with high reliability and established validity. Genes from published association studies in samples of European or European-American descent, and findings from emerging GWASs in predominantly White samples will be tested for association with alcohol dependence in this African-American sample. Positive findings will be further refined by testing for association with other substance dependence, comorbid psychiatric disorders, and phenotypes related to general addiction liability and externalizing behavior. These analyses will allow determination of whether previous association findings for substance dependence are generalizable to the African-American population, and whether association with other population-specific variants is observed in the candidate gene regions. State-of-the art methods will be used to ensure thorough coverage of candidate gene regions, and genomic control SNPs will be used to test for potential population stratification. In summary, this project would be among the first genetic studies of alcohol dependence to focus specifically on African- Americans, thus addressing a significant public health problem in an under-studied and underserved population. The economic costs associated with abuse of alcohol have been estimated at $184 billion per year and excessive alcohol use is one of the top contributors to preventable early mortality in the United States today. Though genetic research holds great promise toward the development of individualized treatment and diagnosis for complex disease such as alcohol dependence, there have been comparatively few genetic studies of alcohol dependence that have focused specifically on African-Americans. To help ensure that the benefits of genetic medicine are realized for this population, the current application seeks to develop a sample of African- Americans with and without alcohol dependence, for targeted genetic studies, using findings from samples of European-descent to guide initial genetic analyses
Keywords: addiction; Address; African American; Age; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Alleles; American; Antisocial Personality Disorder; base; Blood specimen; Candidate Disease Gene; case control; Code; Communities; Complex; Conduct Disorder; Data; Development; Diagnosis; Diagnostic; Disease; disorder risk; Drug Addiction; Drug Modulation; economic cost; Educational aspects; Ensure; Ethanol Metabolism; ethnic difference; Ethnic group; European; Evaluation; Exhibits; externalizing behavior; Family history of; Future; Gender; gene discovery; Gene Frequency; Gene Targeting; Generations; Genes; Genetic; genetic analysis; Genetic Determinism; Genetic Medicine; Genetic Polymorphism; Genetic Research; genome wide association study; Genomics; Genotype; Grant; Health; health disparity; Hylobates Genus; IGA Glomerulonephritis; Individual; Interview; Knowledge; Light; Linkage Disequilibrium; Major Depressive Disorder; Marihuana; Measurement; Mediating; men; Mental disorders; Methods; Mortality Vital Statistics; Neurotransmitters; Nicotine Dependence; novel; Pattern; Personality; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Play; Population; Process; Property; public health medicine (field); Publishing; Race; receptor; Reporting; Research; Resources; Rewards; Risk; Risk Assessment; Risk Factors; Role; Sampling; Signal Transduction; Smoking; socioeconomics; Specificity; stem; Stratification; Structure; Substance Addiction; System; Taste Perception; Testing; Underserved Population; United States; Validation; Variant; Woman; working group
Relevance: The economic costs associated with abuse of alcohol have been estimated at $184 billion per year and excessive alcohol use is one of the top contributors to preventable early mortality in the United States today. Though genetic research holds great promise toward the development of individualized treatment and diagnosis for complex disease such as alcohol dependence, there have been comparatively few genetic studies of alcohol dependence that have focused specifically on African-Americans. To help ensure that the benefits of genetic medicine are realized for this population, the current proposal seeks to develop a sample of African- Americans with and without alcohol dependence, for targeted genetic studies, using findings from samples of European-descent to guide initial genetic analyses
Project start date: 2009-04-20
Project end date: 2014-03-31
Budget start date: 1-APR-2011
Budget end date: 31-MAR-2012
PFA/PA: PA-07-070
5R01AA017444-03 (2011): $606401
PATHOGENESIS AND PREVENTION OF AUTOIMMUNE DIABETES
A Richard
Yale Universitycity: New Haven country: United States (us)
Grant 5R01DK051665-15 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: The development of autoimmunity is caused, in part by a failure of negative regulatory mechanisms which ordinarily prevent these diseases from occurring in non-susceptible individuals. Regulation is imposed by anti-inflammatory cytokines which mediate their action, at least in part through regulatory T cells. TGF-beta is, arguably the most important regulatory cytokine which acts at least in part through regulatory CD4+CD25+FoxP3+ positive T cells, and in part through control of other cell types. In this proposal, we will investigate how signaling of TGF-beta into autoaggressive and other T cells prevents the development of T1D, and how this regulation fails in the autoimmune susceptible NOD mouse. Second, we will determine the cellular origin of the TGF-beta which inhibits T1D development. It has been recently shown that anti-CD3 treatment is therapeutic in reversing T1D in humans that have recently developed Type 1 Diabetes. We will determine whether TGF-beta is instrumental in this process and we will elucidate the mechanism whereby this occurs
Keywords: Address; Anti-inflammatory; Anti-Inflammatory Agents; Antigen-Presenting Cells; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmunity; CD3 Antigens; CD4 Positive T Lymphocytes; CD8B1 gene; cell type; Cells; cytokine; Development; Diabetes Mellitus; Disease; Failure (biologic function); Homeostasis; Human; IL2RA gene; immunoregulation; Inbred NOD Mice; Individual; Insulin-Dependent Diabetes Mellitus; islet; Mediating; Modeling; Mus; Pathogenesis; prevent; Prevention; Process; programs; Regulation; Regulatory T-Lymphocyte; Role; Signal Transduction; Source; T-Lymphocyte; T-Lymphocyte Subsets; Therapeutic; Tissues; Transforming Growth Factor beta; Work
Project start date: 1996-08-01
Project end date: 2012-07-31
Budget start date: 1-AUG-2011
Budget end date: 31-JUL-2012
5R01DK051665-15 (2011): $299361
DETECTION: LUNG IMAGING AND PROFILING
A Richard, Research Associate Professor Of Med
Washington Universitycity: Saint Louis country: United States (us)
Abstract: The defining feature of chronic obstructive pulmonary disease (COPD) is irreversible airflow limitation measured during forced expiration. This results from a varying combination of increased airflow resistance in the small airways and decreased elastic recoil due to emphysematous destruction of lung tissue. We recently showed that significant obstruction of the small airways is present in the lungs of patients with advanced emphysema and that the inflammatory response in the peripheral lung tissue correlates with the severity of COPD as gauged by the GOLD classification scheme. Quantitative analysis of the inflammatory response found strong correlation with the level of lung infiltration by CD8+ T cells, B cells, and macrophages and suggested that these cell types may specially serve to drive the COPD phenotype. Using CT and 3He magnetic resonance imaging (3He MRI) to quantitatively assess regional differences in small airway obstruction and emphysematous destruction in severe COPD, our imaging group has found that regions of mild to moderate disease are found adjacent to sites of severe destruction or obstructive disease even in patients with GOLD 4-stage disease. We hypothesize that the different levels of lesion severity represent different stages in the pathogenesis of the lesions. Our active lung transplantation program, expertise in new imaging technologies and the ability to conduct quantitative analysis of the inflammatory response and tissue remodeling afford a unique opportunity to construct new criteria for assessment of COPD patients. We propose to investigate the pathogenesis of GOLD 4-stage COPD in patients awaiting lung transplant with the following Specific Aims 1) To test the hypothesis that there is progression in both extent and severity of the inflammatory immune process in regions affected by moderate to severe degrees of emphysema and small airway disease, using morphologic analysis and quantitative immunopathology to characterize the inflammatory immune process. 2) To noninvasively quantify the regional extent and severity of disease separately in subjects with severe COPD using 3He MRI and high-resolution CT imaging. 3) To validate the in-vivo and ex-vivo imaging results in Aim II against the histology in Aim I in order to develop a new approach to quantifying both the extent and severity of emphysema and small airways disease within the lungs of individual patients with COPD
Keywords: Affect; Airway Obstruction; Alveolar; alveolar destruction; Aspiration, Respiratory; Attention; B blood cells; B-Cells; B-Lymphocytes; Body Tissues; Breathing; Bursa-Dependent Lymphocytes; Bursa-Equivalent Lymphocyte; CD8; CD8B; CD8B1; CD8B1 gene; cell type; Chronic Obstructive Airway Disease; Chronic Obstructive Lung Disease; Classification Scheme; COAD; Collaborations; COPD; Detection; Disease; disease phenotype; disease severity; disease/disorder; Disorder; Elastin; Emphysema; expiration; Exposure to; Future; Gases; Genetic; Grafting, Lung; heavy metal lead; heavy metal Pb; Heterogeneity; Histology; Image; imaging; Imaging technology; Immune; Immunologic, Immunochemical; Immunologics; immunopathology; in vivo; Individual; Infiltration; Inflammatory; Inflammatory Response; Infrastructure; Inhalation; Inhaling; inspiration; Inspiration, Respiratory; Institution; Lead; Lesion; Link; Lung; lung imaging; Lung Parenchyma; lung scanning; Lung Tissue; Lung Transplantation; Lung volume reduction surgery; LVRS; Lymphoid; LYT3; macrophage; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Matrix Metalloproteinases; Measures; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Methods; Microarray Analysis; microarray technology; Microarray-Based Analysis; MMPs; MR Imaging; MR Tomography; MRI; mucous; Mucous body substance; Mucus; Nature; new approaches; NMR Imaging; NMR Tomography; novel approaches; novel strategies; novel strategy; Nuclear Magnetic Resonance Imaging; Obstruction; Particulate Matter; Pathogenesis; Pathology; Patients; Pb element; Peripheral; Persons; Process; programs; Programs (PT); Programs [Publication Type]; pulmonary; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Pulmonary imaging; regional difference; repair; repaired; Research Infrastructure; Research Resources; Resistance; resistant; Resolution; Resources; Respiratory System, Lung; RNA library; Sampling; Severities; Severity of illness; Site; small airways disease; Staging; Stimulus; Structure; Structure of parenchyma of lung; Surface; T-Cell Subsets; T-Cells; T-Lymphocyte; T-Lymphocyte Subsets; Testing; thymus derived lymphocyte; Thymus-Dependent Lymphocytes; Time; Tissues; transplant; Transplantation; Zeugmatography
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
5P50HL084922-05_0001 (2011): $397393
HIGH THROUGHPUT IN VIVO SCREENING: TRANSLATIONAL GENERATION OF NOVEL ANALGESICS
A Richard, President
Torrey Pines Inst For Molecular Studiescity: Port St. Lucie country: United States (us)
Grant 1R01DA031370-01 from National Institute On Drug Abuse
Abstract: The central working hypothesis of the proposed study is that the direct in vivo high throughput screening (in vivo HTS) will yield enhanced leads, thereby accelerating the discovery of analgesics with improved safety profiles. This work continues the work of the completed R21 (NIDA DA019620) entitled, "In Vivo Screening of Mixture-Based Combinatorial Libraries". The overall approach described herein will accelerate drug discovery and the subsequent identification of more advanced therapeutic candidates poised for preclinical studies. The traditional approach to small molecule drug discovery is to identify individual compounds through in vitro HTS assays, before selected compounds are tested in vivo. However, such a late transition to animal testing fosters a high rate of attrition that is costly in both time and research dollars. To circumvent this problem, this proposal utilizes a novel translational approach capable of eliminating non-efficacious compounds at the earliest stage. The long-term goal of these studies is to apply in vivo HTS to accelerate drug discovery in multiple therapeutic areas. As the first step towards that goal, the specific objective in the present application applies this technique to address the need for potent, but inherently safer, analgesic compounds. Marketed opioid analgesics are both potent and effective, but are strongly addictive with potentially life- threatening side effects. This proposal will identify new chemical entities (NCEs) with the potential to advance to human clinical trials and, if successful, improve patients´ quality of life while reducing the societal problems posed by nonmedical use of opioid analgesics. The potential of this proposal is clearly supportive of the mission of NIDA, "to lead the Nation in bringing the power of science to bear on drug abuse and addiction." The research design uses a method of screening large, mixture-based libraries in vivo to identify compounds that are active in an in vivo mouse model of nociception. A total of 37 available, in-house, small molecule library mixtures (representing over 7 million small molecules) will be screened in vivo with animal models of antinociception to identify additional scaffolds for development, complementing a previously identified scaffold. Individual compounds selected from these three scaffolds will be synthesized and purified for additional development which will include in vitro analysis, pharmaceutical profiling, and additional in vivo models. Ultimately, we will examine multiple scaffolds and select 2-3 new chemical entities to initiate preclinical studies. By the end of the proposed study, we will have clearly demonstrated the utility of combining large mixture- based libraries of small molecules with in vivo screening (in vivo HTS) to identify therapeutic hits and leads with demonstrated efficacy and minimized side effects. By utilizing in vivo HTS, compounds may be identified with in vivo efficacies that function through previously unidentified biological pathways, providing potential advances in both the clinical and scientific realms. This proposal utilizes a new methodology which has the potential to accelerate drug discovery in multiple therapeutic areas. Highly innovative approaches now permit literally millions of compounds to be tested in animal models at a very early stage of the discovery process. Initial studies will be targeted toward the identification of small molecules useful for the treatment of pain and that lack the negative effects of existing pain medications (addiction potential, respiratory depression, tolerance and psychological effects)
Keywords: Acute; addiction; Address; Adverse effects; Agonist; Analgesics; Animal Model; Animal Testing; Area; base; Biological; Biological Assay; Biological Sciences; Chemicals; Clinical; Clinical Trials; combinatorial; Complement; Constipation; Cyclic AMP; Data; Development; Dose; Drug abuse; Drug Addiction; drug discovery; Evaluation; Exhibits; Fostering; Gastrointestinal Transit; Generations; Goals; high throughput screening; Housing; Human; improved; In Vitro; in vitro activity; in vitro Assay; in vitro testing; in vivo; in vivo Model; Individual; inflammatory neuropathic pain; innovation; interest; Lead; Libraries; Life; Marketing; Measures; Methodology; Methods; Mission; mouse model; Narcotic Antagonists; National Institute of Drug Abuse; National Institute of Mental Health (U.S.); Nociception; nonmedical use; novel; Opioid; Opioid Analgesics; Pain; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmacologic Substance; Positioning Attribute; pre-clinical; Preclinical Drug Evaluation; preclinical study; preference; Principal Investigator; Process; Property; psychologic; Psychotropic Drugs; Quality of life; receptor internalization; Research; Research Design; Respiration; respiratory; response; Route; Safety; scaffold; Scanning; Science; Screening procedure; small molecule; small molecule libraries; Solubility; Staging; Tail; Techniques; Testing; Therapeutic; Time; translational approach; Ursidae Family; Ventilatory Depression; Water; Withdrawal; Work
Relevance: This proposal utilizes a new methodology which has the potential to accelerate drug discovery in multiple therapeutic areas. Highly innovative approaches now permit literally millions of compounds to be tested in animal models at a very early stage of the discovery process. Initial studies will be targeted toward the identification of small molecules useful for the treatment of pain and that lack the negative effects of existing pain medications (addiction potential, respiratory depression, tolerance and psychological effects)
Project start date: 2011-08-01
Project end date: 2016-05-31
Budget start date: 1-AUG-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-10-067
1R01DA031370-01 (2011): $407964
A BRIEF, CLINIC-BASED, HIV PREVENTION PROGRAM FOR AFRICAN AMERICAN TEEN MALES
A Richard, Professor
University Of Kentuckycity: Lexington country: United States (us)
Grant 5R01MH083621-04 from National Institute Of Mental Health
Abstract: The Centers for Disease Control and Prevention has declared that AIDS is a "state of emergency" in the US relative to African Americans. Teen males attending STD clinics are one important, yet often neglected, population of African Americans at risk of HIV acquisition. Despite extremely high rates of STD acquisition (and subsequent infection) among this population, effective clinic-based interventions specifically designed to reduce their sexual risk behavior for STD/HIV have not been developed/disseminated. A recent intervention trial (conducted by Dr. Crosby) demonstrated the efficacy of a brief, clinic-based, intervention designed to prevent subsequent STI acquisition among African American males 18 to 29 years of age. The proposed study will test the efficacy this intervention (in modified form) to reduce STI incidence among African American teen (15 to 20 years old). The primary hypothesis is that teens randomized to receive the intervention will have a lower incidence rate of laboratory-confirmed STIs at 2 and 6-month follow-up assessments (as well as 12-month follow-up conducted by a medical records review) compared to those receiving an attention-equivalent control condition. Teens (N = 840) will be recruited from a publicly-funded STD clinic located in an urban area of the South. After completing an A-CASI assessment, teens will be rated on their ability to apply condoms to a penile model and then asked to donate a urine specimen for STI testing. Specimens will be tested for C. trachomatis, N. gonorrhoeae, and T. Vaginalis using nucleic acid amplification assays. Randomization will then be achieved by a concealment of allocation technique. Teens will be randomized to immediately receive 1) a brief (60 minute) theory-based, one-on-one, interactive intervention delivered by a lay health advisor or 2) an attention equivalent control condition. The assessment battery will be repeated 2 months subsequent to enrollment and again 6 months after enrollment. A medical records review will be conducted 12 months after enrollment to compare clinic reported incidence rates between the randomized groups of teens. If incidence of STIs in this population of teens can be decreased as substantially as was found in the previous study of 18 to 29 year-old African American males (percent relative difference = 36.7), the public health significance for African American teen males will substantially contribute to rectify the racial disparity in HIV/STD experienced by African American teen males. By extension, we suggest that their partners (typically African American teen females) will also benefit. Because our program is designed for ease of implementation, the number of dissemination and translation issues will be greatly minimized thereby greatly facilitating the process of translating research into practice. The proposed efficacy trial tests an innovative method of bridging the gap between research and practice. By providing a brief, clinic-based, HIV/STD prevention program to African American teen males attending an STD clinic, the study will be the first to demonstrate that teen´s sexual risk behavior can be reduced without excessive time and resources. The focus on African American teen males is also quite timely given the recent declaration by CDC that AIDS is a "state of emergency" for African Americans
Keywords: 20 year old; Acquired Immunodeficiency Syndrome; African American; Age-Years; arm; Attention; avoid sex; base; Biological Assay; Brothers; Caring; Centers for Disease Control and Prevention (U.S.); Chlamydia; Clinic; condoms; design; disorder prevention; effective intervention; efficacy testing; efficacy trial; Emergency Situation; Enrollment; experience; Female; flexibility; follow-up; Frequencies (time pattern); Funding; Future; Glare; Goals; Gonorrhea; Health; Health Educators; high risk men; Hispanics; HIV; improved; Incidence; Infection; innovation; Instruction; Intervention; intervention effect; intervention program; Intervention Trial; Kentucky; Laboratories; Life; Low income; male; man; Medical Records; medical specialties; men; Methods; Modeling; neglect; Neisseria gonorrhoeae; Newly Diagnosed; Nucleic Acids; Perception; Population; post intervention; prevent; Prevention program; Process; programs; public health medicine (field); Randomized; Randomized Controlled Trials; Recruitment Activity; Relative (related person); Reporting; Research; Research Design; research to practice; Resources; response; Risk; safer sex; Science; Services; sex; Sex Behavior; sex risk; Sexual Partners; Specimen; Techniques; Teenagers; Testing; theories; therapy design; Time; Translating; Translational Research; Translations; Treatment Efficacy; Trichomonas Infections; Trichomonas vaginalis; Uncertainty; United States; urban area; Urine; Vagina; Woman; Work
Project start date: 2008-09-30
Project end date: 2013-05-31
Budget start date: 1-JUN-2011
Budget end date: 31-MAY-2012
PFA/PA: PAR-07-379
5R01MH083621-04 (2011): $362588
A BRIEF, CLINIC-BASED, SAFER SEX PROGRAM FOR YOUNG AFRICAN AMERICAN MEN WHO HAVE
A Richard, Professor
University Of Kentuckycity: Lexington country: United States (us)
Grant 1R01MH092226-01A1 from National Institute Of Mental Health
Abstract: The Centers for Disease Control and Prevention (CDC) has termed AIDS a "health crisis" for African Americans and has called for a heightened national response. The crisis is especially dramatic in the South and it is now apparent that young African American men who have sex with men (MSM) are exceedingly likely to be infected. Unfortunately, the ever-expanding HIV epidemic experienced by this population has not been matched by equal attention to the development of efficacious prevention programs. The proposed project expands upon an NIMH-funded study (R21 MH066682-01A1) conducted by Dr. Crosby. His study of young African American males found that a brief, clinic-based intervention reduced incidence of subsequent STDs by about 50%. This brief, one-on-one, intervention program, known as Focus on the Future (FOF), is a practical alternative to group-based safer sex programs that can be difficult to translate from science into practice. The program is now classified as a "Best Practice" intervention by CDC. This project will begin with an extensive formative phase designed to adapt FOF to MSM. The adapted program will seek to "sexualize" condoms to promote their consistent and correct use to better prevent STD/HIV. The program is uniquely flexible in that it can be applied to MSM regardless of their HIV serostatus. The adapted program will be tested by a two-arm efficacy trail. We will recruit 750 MSM (15-29 years of age) from a publicly-funded STD clinic in Jackson MS. Men in the treatment condition will be compared to men receiving the control condition comprised of standard of care counseling from the clinic plus a free ditty bag of supplies from the "condom and lube buffet" (condom/lube distribution). The trial will test five hypotheses. Men randomized to receive the intervention will 1) have a lower incidence rate of laboratory-confirmed STDs (by urine assay and rectal swab) at each of three follow-up assessments (3, 6, and 12 months) compared to controls; 2) report significantly fewer acts of unprotected penetrative sex (penile-vaginal or penile-anal) between follow-up assessments compared to controls; 3) report having significantly fewer unprotected penetrative (penile-vaginal or penile-anal) sex partners between follow-up assessments compared to controls; 4) report having significantly fewer negative experiences with condom use between follow-up assessments compared to controls; and 5) demonstrate significantly greater improvement in condom application skills, throughout the 12-month study, compared to those receiving the control condition. Given the dearth of evidence-based options for intervening with this vulnerable population in clinical settings, demonstrated efficacy of the adapted program has important implications for public health efforts to prevent STD/HIV. The adapted FOF is also directly responsive to the President´s National HIV/AIDS strategy, particularly with regards to the target population of this proposal. The proposed efficacy trial will occur in Jackson, MS and it tests a brief, clinic-based, HIV/STD prevention program adapted specifically for young African American MSM. This program is based on a CDC-classified Evidenced-Based Intervention known as Focus on the Future. The randomized trial is designed with 3 follow-up assessments and it uses biomarker outcomes as well as a novel method of collecting self-reported outcomes
Keywords: Acquired Immunodeficiency Syndrome; African American; Age-Years; Anal Sex; Anus; arm; Attention; base; Behavior; Biological Assay; biomarker; Centers for Disease Control and Prevention (U.S.); Chlamydia; Clinic; Clinical; clinical practice; condoms; Counseling; design; Development; disorder prevention; effective intervention; efficacy testing; efficacy trial; Enrollment; Epidemic; evidence base; Evidence based intervention; experience; flexibility; follow-up; Funding; Future; Gays; Glare; Gonorrhea; Health; Heart; high risk men; Hispanics; HIV; Incidence; inclusion criteria; Intervention; intervention effect; intervention program; Laboratories; male; men; men who have sex with men; Methods; Modeling; National Institute of Mental Health (U.S.); novel; Outcome; Patient Self-Report; Phase; Population; post intervention; prevent; Prevention program; programs; public health medicine (field); Randomized; Randomized Controlled Trials; randomized trial; Recruitment Activity; rectal; Relative (related person); Reporting; Research; Research Design; response; Risk; safer sex; Sampling; Science; sex; Sexual Partners; skills; standard of care; Swab; Syphilis; Target Populations; Testing; theories; therapy design; Translating; transmission process; Trichomonas Infections; two-arm study; Urine; Vagina; Vulnerable Populations
Relevance: The proposed efficacy trial will occur in Jackson, MS and it tests a brief, clinic-based, HIV/STD prevention program adapted specifically for young African American MSM. This program is based on a CDC-classified Evidenced-Based Intervention known as Focus on the Future. The randomized trial is designed with 3 follow-up assessments and it uses biomarker outcomes as well as a novel method of collecting self-reported outcomes
Project start date: 2011-08-01
Project end date: 2016-05-31
Budget start date: 1-AUG-2011
Budget end date: 31-MAY-2012
PFA/PA: PA-10-067
1R01MH092226-01A1 (2011): $592317
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