The cellular response to injury and inflammation is a fundamental component of several major human diseases. In this proposal, 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. The proposal encompasses four major steps. First, the investigators will use microarray-based methods to identify major genes involved in the responses of selected cell types to defined inflammatory or injurious stimuli. Second, the investigators will screen these genes for DNA sequence polymorphisms. Additional candidate genes selected by clinical criteria or by a polymorphism prediction algorithm will also be screened. Third, the investigators will perform association studies to assess the clinical significance of these polymorphisms. Fourth, the investigators will develop reagents (antibodies and peptides) with which to perform functional studies of a selected subset of these genes. The program is organized as a linear sequence of steps, in which the output from one project provides an experimental basis for the following project. Since each project is guided by the results of the preceding project, the cumulative output of the integrated Program in Genomic Applications (PGA) is far more valuable than what could be achieved by each project in isolation. The central biological theme of the program is inflammation and tissue remodeling, to be studied explicitly in the clinical context of cardiovascular disease. There is a strong rationale for this particular focus, based on four fundamental considerations. First, inflammation and tissue remodeling are biological processes pertinent to many clinical disorders. Although selected features of these processes may be unique to a given tissue or disease context, other aspects will prove to be universal. Thus, reagents developed for allelotyping and functional assessment of gene products produced from polymorphic genes will find broad application in heart, lung and blood research. Second, by studying inflammation and tissue remodeling in the specific context of cardiovascular diseases, the investigators attack those conditions that represent leading causes of death and disability among Americans today. Third, this particular focus will allow the investigators to amplify the impact of funds provided by the PGA, by linking this proposal to the recently funded Reynolds grant to Southwestern that will provide a unique tissue remodeling are complex biological processes that are ideally suited to a genomic scale approach.
The aims and experimental design of this PGA are therefore highly congruent with the RFA solicitation.
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