The overall goal of the Animal/Proteomic Component of the """"""""Applied Genomic Program in Cardiopulmonary Disease"""""""" is to define and test the relevance of disease specific gene candidates that predict lung and cardiac remodeling in animal models of cardiopulmonary diseases utilizing gene profiling approaches. Identification of susceptibility genes for human disease is hampered by variability in clinical phenotype, genetic heterogeneity in human populations and the experimental difficulty in addressing the molecular mechanisms underlying complex pathological processes in humans. Thus our strategy is to take advantage of the experimental tractability of murine models of disease to provide high quality of candidate genes underlying remodeling processes in multiple cardiopulmonary disease. To achieve this goal, we have assembled an outstanding group of investigators with broad and overlapping expertise with animal models of cardiopulmonary diseases including asthma, pulmonary fibrosis, cardiac failure, emphysema, hyperoxia-induced lung injury and pulmonary hypertension. Our preliminary data suggest that these models are predictive of human disease and that the gene profiling approach can successfully be used to identify genes important in human disease.
The specific aims of this component are l) to define a set of predictor genes for tissue remodeling using Affymetrix 5000 predictor oligonucleotide microarrays (Mu19K) in each of the six animal models of disease; 2) to refine the number of candidate genes and to establish the kinetics of gene expression by constructing custom cDNA arrays for 1000-5000 predictor genes in each model; and 3) to compare and contract gene expression profiles between models and human systems in order to prioritize candidates for further analysis by proteomic and single nucleotide polymorphism (SNPs) approaches; 4) to utilize proteomic approaches to study the consequences of changes in gene expression at the cell and tissue level; and 5) to being to determine the functional relevance of this focused set of genes to remodeling processes by utilizing transgenic and knockout technologies. The combined (mouse and human) approach of this program to the identification of disease specific genes for lung and cardiac remodeling should greatly facilitate future disease discovery.
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