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PROGRAMS FOR GENOMIC APPLICATIONS National Heart, Lung, and Blood Institutes National Institutes of Health Mission Statement One of the primary missions of the NHLBI PGA program is to develop resources and reagents for dissemination to the broader community of investigators involved in NHLBI-related research areas. Goal Aid clinician/scientists in: Developing information, tools, and resources to link genes to biological function on a genomic scale. All the information, reagents, and tools developed in the PGAs will be freely available in a timely manner to the research community. PGAs will provide workshops, courses, and visiting scientist programs to facilitate the training of researchers in the use of the data and related technologies developed by the PGAs. The PGA Web site will provide a central place to learn about the PGA Program and access to PGA-developed resources through links to the individual PGA sites. This web site will be updated periodically to provide the most recent information available on this NHLBI program. Organizational Structure Coordinating Committee Bioinformatics Subcommittee Phenotype Subcommittee Proteomics Subcommittee Microarray Subcommittee Data Sharing Subcommittee Integration Subcommittee Education Subcommittee PGA Listings Applied Genomics in Cardio-Pulmonary Disease Mouse Models of Heart, Lung, and Blood Diseases Johns Hopkins University School of Medicine Genomics of Cardiovascular Development, Adaptation, & Remodeling Harvard Medical School Physiogenomics of Stressors in Derived Consomic Rats Medical College of Wisconsin The Jackson Laboratory Expression Profiling of Rodent Models of Human Disease The Institute for Genomics Research Comparative Genomic Analysis of Cardiovascular Genes Genomics of Proteomics of Cell Injury and Inflammation Lawrence Berkeley National Laboratory University of Texas S.W. Medical Center Harvard Medical School Innate Immunity in Heart, Lung, and Blood Diseases NHLBI Bay Area Functional Genomic Consortium The University of Arizona The David J. Gladstone Institute UW-FHCRC Variation Discovery Resource University of Washington Genomic Analysis of Stress and Inflammation Bioinformatics Carol Bult, Ph.D., The Jackson Laboratory Data Sharing Isaac Kohane, M.D., Ph.D., Harvard Medical School Education Scott Weiss, M.D., M.S., Harvard Medical School Genomic Inventory/Integration Edward Rubin, M.D., Ph.D., The Lawrence Berkeley National Laboratory Microarray John Quackenbush, Ph.D., The Institute for Genomics Research Phenotype Allen Cowley, Jr., Ph.D., Medical College of Wisconsin Proteomics Thomas Kodadek, Ph.D., Univ. Texas S.W. Medical Center Subcommittee Chairs PGA Resources The kinds of resources that are anticipated as a result of this program include the following: • • • • • • • Microarrays DNA Variations (SNPs and their locations, genotypes, allele frequencies, and haplotypes) Mouse models of HLBS disorders Rat models of HLBS disorders Reagents (sequences, amplification primers, clones or clone sets, antibodies, mice, and rats) Protocols Bioinformatic Resources (software tools and databases) PGA Tools Arrays data SNPs gene types animals models phenotyping tissue banks population data The NHLBI Bay Area Functional Genomics Consortium http://baygenomics.ucsf.edu The investigators will use gene-trap vectors to inactivate thousands of genes in mouse embryonic stem (ES) cells and make them freely available for the purpose of generating knockout mice. PI: Dr. Stephen G. Young The NHLBI Bay Area Functional Genomics Consortium Tools: Mouse embryonic stem cells carrying insertional mutations In situ hybridization images of novel genes from the library of genes disrupted by insertional mutations Bioinformatics analyses of novel genes disrupted by insertional mutations Microarray experiments defining the potential importance of novel sequences in cardiopulmonary diseases Knockout mice will be made from embryonic stem cells carrying insertional mutations http://baygenomics.ucsf.edu Genomics of Cardiovascular Development, Adaptation, and Remodeling http://www.cardiogenomics.org The goal of this PGA is to begin linking genes to function, dysfunction and structural abnormalities of the cardiovascular system caused by clinically relevant, genetic and environmental stimuli. The principal biological theme to be pursued is how the transcriptional network of the cardiovascular system responds to genetic and environmental stresses to maintain normal function and structure, and how this network is altered in disease. PI: Dr. Seigo Izumo Genomics of Cardiovascular Development, Adaptation, and Remodeling http://www.cardiogenomics.org Tools: Microarray Data: Gene expression profiles of mouse models of cardiomyopathies Gene expression profiles of normal mouse hearts Gene expression profiles of human tissues from heart failure patients Benchmark Data Sets: Phenotypic characterization of mouse models of cardiomyopathies containing genetic background, ECG, MRI, Echo data, and selected histology images for each model Genomics of Cardiovascular Development, Adaptation, and Remodeling http://www.cardiogenomics.org Tools: (cont.) SNP Data: Sequence and SNP data of mutation screens in human congenital heart disease and cardiomyopathy Reagents: Full-length cDNA clones of human genes involved in heart development and disease states Human tissue bank of 290 samples derived from cardiac transplantations or organ harvests Bioinformatics Resources (databases and software): Clustering software available over a web portal Applied Genomics in Cardiopulmonary Disease http://www.hopkins-genomics.org Cardiopulmonary disease, the most prevalent cause of significant morbidity and mortality in the United States -represents a spectrum of many acute and chronic pathologic processes. The focus of this PGA is to define a subset of genes, derived from gene expression profiles, which are associated with pathogenic tissue remodeling in these clinical disorders. PI: Dr. Joe G.N. Garcia Applied Genomics in Cardiopulmonary Disease http://www.hopkins-genomics.org Tools Reagents / Materials: Human and Animal Protocols for the ten disorders studied Microarrays: Custom disease-specific human cDNA microarray chips and murine chips for the ten disorders studied. Mouse models: from patients with cardiopulmonary disease (asthma, COPD, adult cystic fibrosis, lung transplantation, acute lung injury (ARDS), scleroderma, sarcoidosis, pulmonary hypertension, ischemic cardiomyopathy, cardiac transplant). Murine model of asthma, bleomycin (pulmonary fibrosis), hypertrophic cardiomyopathy, emphysema/Marfan syndrome, hyperoxic lung injury (ARDS) Rat models: Monocrotaline-induced pulmonary hypertension. Innate Immunity in Heart, Lung, and Blood Disease http://innateimmunity.net SNP variation discovery technologies will be used to screen for polymorphisms in 50 genes known to be directly or indirectly related to the innate immune response. We will then genotype a sample of individuals of Hispanic, nonHispanic White, and African American ethnicity for a proportion of the newly discovered polymorphisms. Association analyses will be performed to identify SNPs most likely to be involved in the determination of asthma, chronic obstructive pulmonary disease, myocardial infarction and deep venous thrombosis and to examine ethnic diversity. PI: Dr. Fernando D. Martinez Mouse Models of Heart, Lung, and Blood Diseases http://pga.jax.org The goal in this PGA is to link genetic variation to biological function and dysfunction. Using a phenotypedriven approach, we will identify genetic mechanisms underlying the physiology and pathophysiology of atherosclerosis, hypertension, lung function, blood formation, thrombosis, obesity, inflammation, and sleep function. PI: Dr. Luanne L. Peters Genomic Analysis of Stress and Inflammation http://genetics.mgh.harvard.edu/Parabiosys/index.html The investigators in this program propose to identify and characterize gene networks activated by pro-inflammatory, metabolic, and pathogen stresses affecting the cardiovascular system and the lung. Stress-activated pathways play central roles in the pathophysiology of some of the most important diseases addressed by the National Heart, Lung and Blood Institute, including atherosclerosis, pulmonary infection, cystic fibrosis, and heart failure. The exploration of these pathways is likely to result in the generation of fundamentally new insights into these disorders. PI: Dr. Brian Seed Comparative Genomic Analysis of Cardiovascular Gene Regulation http://pga.lbl.gov The central goal of this PGA will be to use a comparative genomic approach first to identify, and then to determine the function of elements regulating the expression of genes affecting the CV system. The activities of this PGA are not centered on the discovery of new genes, but rather upon using comparative genomics to understand the role of cis regulating elements in the expression of genes already being studied by CV researchers. PI: Dr. Edward M. Rubin Physiogenomics of Stressors in Derived Consomic Rats http://pga.mcw.edu To obtain maximum utility of the Human Genome Project there is a critical need to define the function of as many genes as possible as rapidly as possible. Genes that contribute to common disease are priorities. This PGA is engaged in a powerful approach to dissect multigenic common diseases through the development of panels of chromosomal substitution strains of rats (consomic rat panels). PI: Dr. Howard J. Jacobs UW-FHCRC Variation Discovery Resource http://pga.mbt.washington.edu The goal of this PGA is to identify the common variable sites, establish their relative frequencies and haplotypes in two human populations having different evolutionary history to expand the resources available to explore inter-individual variation in this response and its relationship to disease risk, outcome and treatments in common human disorders. Education and training on sequence variation analysis is also a priority, and a hands-on workshop in variation discovery and analysis is planned. PI: Dr. Deborah A. Nickerson Genomics and Proteomics of Cell Injury and Inflammation http://pga.swmed.edu In this PGA, the investigators will seek to elucidate the basic mechanisms underlying these responses through a combination of genomic and proteomic approaches linking the responses to the genes and proteins involved. For the purposes of this proposal, injury is defined in the broadest sense and will encompass diverse, clinically relevant, pathogenic stimuli. PI: Dr. Stephen J. Johnston Microarray Expression Profiling of Rodent Models of Human Disease http://pga.tigr.org Disease phenotypes arise from complex interactions of organisms with their environments. While we have a long history of associating genes and gene defects with a large array of disease phenotypes, a growing body of data suggests that many disease phenotypes arise from the interactions of genes with their environments, including the genetic background in which the genes are expressed. The goal of this PGA is to begin exploration of these interactions using rodent models of human disease and cDNA microarray assays to elucidate patterns of gene expression in heart, lung, blood, and sleep disorders. PI: Dr. John Quackenbush NIH PGA Research Network • SeattleSNPs - Seattle . • PhysGen - Milwaukee . • BayGenomics .. • PGA CompGen - San Francisco - Berkeley . . • InnateImmunity - Tucson • Southwestern - Dallas . • JAX PGA . •• CardioGenomics ParaBioSys Bar Harbor Boston - Boston .. • HopGenes - Baltimore • TREX - Rockville NIH PGA Websites PROGRAMS FOR GENOMIC APPLICATIONS http://www.nhlbi.nih.gov/resources/pga/index.htm NIH PGA Websites (cont.) BayGenomics - http://baygenomics.ucsf.edu CardioGenomics - http://www.cardiogenomics.org HopGenes - http://www.hopkins-genomics.org InnateImmunity - http://innateimmunity.net JAX PGA - http://pga.jax.org ParaBioSys - http://genetics.mgh.harvard.edu/Parabiosys/index.html NIH PGA Websites (cont.) PGA CompGen - http://pga.lbl.gov PhysGen - http://pga.mcw.edu SeattleSNPs - http://pga.mbt.washington.edu Southwestern - http://pga.swmed.edu TREX - http://pga.tigr.org