Transcript No Slide Title

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:
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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
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gene types
animals models
phenotyping
tissue banks
population data
The NHLBI Bay Area Functional
Genomics Consortium http://baygenomics.ucsf.edu
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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:
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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:
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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
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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.)
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SNP Data:
 Sequence and SNP data of mutation screens in human congenital
heart disease and cardiomyopathy
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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
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Bioinformatics Resources (databases and software):
 Clustering software available over a web portal
Applied Genomics in Cardiopulmonary
Disease
http://www.hopkins-genomics.org
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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.
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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
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Reagents / Materials:
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Human and Animal Protocols for the ten disorders studied
Microarrays:
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Custom disease-specific human cDNA microarray chips and murine chips for the
ten disorders studied.
Mouse models:
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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:
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Monocrotaline-induced pulmonary hypertension.
Innate Immunity in Heart, Lung,
and Blood Disease
http://innateimmunity.net
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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
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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
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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
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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.
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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
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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
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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
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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