PPROGRAMS FORROGRAMS FOR

GGENOMIC ENOMIC AAPPLICATIONSPPLICATIONS

National Heart, Lung, and Blood InstitutesNational Institutes of Health

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.

Mission StatementMission Statement

Aid clinician/scientists in: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 periodicallyto provide the most recent information available on this NHLBI program.

GoalGoal

Organizational StructureOrganizational Structure

Coordinating CommitteeCoordinating Committee

BioinformaticsSubcommittee

ProteomicsSubcommittee

Data SharingSubcommittee

EducationSubcommittee

IntegrationSubcommittee

MicroarraySubcommittee

PhenotypeSubcommittee

Applied Genomics in Cardio-Pulmonary DiseaseApplied Genomics in Cardio-Pulmonary DiseaseJohns Hopkins University School of Medicine

Genomics of Cardiovascular Development, Genomics of Cardiovascular Development, Adaptation, & RemodelingAdaptation, & RemodelingHarvard Medical School

Physiogenomics of Stressors in Derived Physiogenomics of Stressors in Derived Consomic RatsConsomic RatsMedical College of Wisconsin

Genomics of Proteomics of Cell Injury and Genomics of Proteomics of Cell Injury and InflammationInflammationUniversity of Texas S.W. Medical Center

Innate Immunity in Heart, Lung, and Blood Innate Immunity in Heart, Lung, and Blood DiseasesDiseasesThe University of Arizona

UW-FHCRC Variation Discovery ResourceUW-FHCRC Variation Discovery ResourceUniversity of Washington

PGA ListingsPGA ListingsMouse Models of Heart, Lung, and Blood Mouse Models of Heart, Lung, and Blood DiseasesDiseasesThe Jackson Laboratory

Expression Profiling of Rodent Models of Expression Profiling of Rodent Models of Human DiseaseHuman DiseaseThe Institute for Genomics Research

Comparative Genomic Analysis of Comparative Genomic Analysis of Cardiovascular GenesCardiovascular GenesLawrence Berkeley National Laboratory

Genomic Analysis of Stress and InflammationGenomic Analysis of Stress and InflammationHarvard Medical School

NHLBI Bay Area Functional Genomic NHLBI Bay Area Functional Genomic ConsortiumConsortiumThe David J. Gladstone Institute

BioinformaticsBioinformatics Carol Bult, Ph.D., The Jackson Laboratory

Data SharingData Sharing Isaac Kohane, M.D., Ph.D., Harvard Medical School

EducationEducation Scott Weiss, M.D., M.S., Harvard Medical School

Genomic Inventory/IntegrationGenomic Inventory/Integration Edward Rubin, M.D., Ph.D., The Lawrence Berkeley National

Laboratory

MicroarrayMicroarray John Quackenbush, Ph.D., The Institute for Genomics

Research

PhenotypePhenotype Allen Cowley, Jr., Ph.D., Medical College of Wisconsin

ProteomicsProteomics Thomas Kodadek, Ph.D., Univ. Texas S.W. Medical Center

SubcommitteeSubcommitteeChairsChairs

PGA ResourcesPGA Resources

The kinds of resources that are anticipated as a result of thisprogram 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)

Arrays data

SNPs gene types animals models phenotyping tissue banks population data

PGA ToolsPGA Tools

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.

The NHLBI Bay Area Functional The NHLBI Bay Area Functional Genomics ConsortiumGenomics Consortium http://baygenomics.ucsf.edu

PI: Dr. Stephen G. Young

Tools: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

The NHLBI Bay Area Functional The NHLBI Bay Area Functional Genomics ConsortiumGenomics Consortium

http://baygenomics.ucsf.edu

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 howthis network is altered in disease.

Genomics of Cardiovascular Development, Genomics of Cardiovascular Development, Adaptation, and RemodelingAdaptation, and Remodeling

http://www.cardiogenomics.org

PI: Dr. Seigo Izumo

Tools: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, Genomics of Cardiovascular Development, Adaptation, and RemodelingAdaptation, and Remodeling

http://www.cardiogenomics.org

Tools: (cont.)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

Genomics of Cardiovascular Development, Genomics of Cardiovascular Development, Adaptation, and RemodelingAdaptation, and Remodeling

http://www.cardiogenomics.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.

Applied Genomics in Cardiopulmonary Applied Genomics in Cardiopulmonary DiseaseDisease http://www.hopkins-genomics.org

PI: Dr. Joe G.N. Garcia

ToolsTools Reagents / Materials:

from patients with cardiopulmonary disease (asthma, COPD, adult cystic fibrosis, lung transplantation, acute lung injury (ARDS), scleroderma, sarcoidosis, pulmonary hypertension, ischemic cardiomyopathy, cardiac transplant).

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: Murine model of asthma, bleomycin (pulmonary fibrosis), hypertrophic

cardiomyopathy, emphysema/Marfan syndrome, hyperoxic lung injury (ARDS)

Rat models: Monocrotaline-induced pulmonary hypertension.

Applied Genomics in Cardiopulmonary Applied Genomics in Cardiopulmonary DiseaseDisease http://www.hopkins-genomics.org

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, non-Hispanic 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 thrombosisand to examine ethnic diversity.

Innate Immunity in Heart, Lung, Innate Immunity in Heart, Lung, and Blood Diseaseand Blood Disease http://innateimmunity.net

PI: Dr. Fernando D. Martinez

The goal in this PGA is to link genetic variation to biological function and dysfunction. Using a phenotype-driven approach, we will identify genetic mechanisms underlying the physiology and pathophysiology of atherosclerosis, hypertension, lung function, blood formation, thrombosis, obesity, inflammation, and sleep function.

Mouse Models of Heart, Lung, Mouse Models of Heart, Lung, and Blood Diseasesand Blood Diseases http://pga.jax.org

PI: Dr. Luanne L. Peters

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.

Genomic Analysis of Stress Genomic Analysis of Stress and Inflammationand Inflammationhttp://genetics.mgh.harvard.edu/Parabiosys/index.html

PI: Dr. Brian Seed

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.

Comparative Genomic Analysis of Comparative Genomic Analysis of Cardiovascular Gene RegulationCardiovascular Gene Regulation

http://pga.lbl.gov

PI: Dr. Edward M. Rubin

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).

Physiogenomics of Stressors in Derived Physiogenomics of Stressors in Derived Consomic RatsConsomic Rats http://pga.mcw.edu

PI: Dr. Howard J. Jacobs

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.

UW-FHCRC Variation Discovery ResourceUW-FHCRC Variation Discovery Resourcehttp://pga.mbt.washington.edu

PI: Dr. Deborah A. Nickerson

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.

Genomics and Proteomics of Cell Genomics and Proteomics of Cell Injury and InflammationInjury and Inflammation http://pga.swmed.edu

PI: Dr. Stephen J. Johnston

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 patternsof gene expression in heart, lung, blood, and sleepdisorders.

Microarray Expression Profiling of Rodent Microarray Expression Profiling of Rodent Models of Human DiseaseModels of Human Disease http://pga.tigr.org

PI: Dr. John Quackenbush

NIH PGA Research NetworkNIH PGA Research Network

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• HopGenes - HopGenes - BaltimoreBaltimore

• CardioGenomics - CardioGenomics - BostonBoston

• PhysGen - PhysGen - MilwaukeeMilwaukee

• Southwestern - Southwestern - DallasDallas

• InnateImmunityInnateImmunity- Tucson- Tucson

• SeattleSNPs SeattleSNPs - Seattle- Seattle

• JAX PGA - JAX PGA - Bar HarborBar Harbor

• TREX - TREX - RockvilleRockville

• PGA CompGenPGA CompGen- - BerkeleyBerkeley

• ParaBioSys ParaBioSys - Boston- Boston

• BayGenomicsBayGenomics- San Francisco- San Francisco

NIH PGA WebsitesNIH PGA Websites

http://www.nhlbi.nih.gov/resources/pga/index.htm

PPROGRAMSROGRAMS FORFOR G GENOMICENOMIC A APPLICATIONSPPLICATIONS

NIH PGA Websites NIH PGA Websites (cont.)(cont.)

BayGenomics - BayGenomics - http://baygenomics.ucsf.edu

CardioGenomics - CardioGenomics - http://www.cardiogenomics.org

ParaBioSys - ParaBioSys - http://genetics.mgh.harvard.edu/Parabiosys/index.html

JAX PGA - JAX PGA - http://pga.jax.org

HopGenes - HopGenes - http://www.hopkins-genomics.org

InnateImmunity - InnateImmunity - http://innateimmunity.net

PGA CompGen - PGA CompGen - http://pga.lbl.gov

TREX - TREX - http://pga.tigr.org

PhysGen - PhysGen - http://pga.mcw.edu

NIH PGA Websites NIH PGA Websites (cont.)(cont.)

Southwestern - Southwestern - http://pga.swmed.edu

SeattleSNPs - SeattleSNPs - http://pga.mbt.washington.edu