Cardiac remodeling is a central feature of human heart failure and shows substantial variation in human subjects. A decade of research in murine models and research in humans performed by the Principal Investigator show that a discreet set of cardiac transcription factors integrate stress signals to cause cardiac remodeling. Our central hypothesis is that common genetic variation in a core set of cardiac transcription factors (MEF2, NKX, NFAT, GATA, FOX) is in large part responsible for the variable course of cardiac remodeling in humans. We will address this hypothesis by performing SNP- and haplotype-based association studies of candidate transcription factors in two existing cohort studies that capture the common phenotypes of remodeling encountered in clinical practice.
In Aim 1 we will test the hypothesis that variation in candidate transcription factors is associated with concentric cardiac remodeling in the Chronic Renal Insufficiency Cohort study (CRIC), a large cohort with a high prevalence of concentric remodeling.
In Aim 2 we will perform similar analyses in the Penn Heart Failure Study, a large single-center cohort initiated by the applicant with a high prevalence of eccentric remodeling.
In aim 3 we will collaborate with an expert molecular biologist at Penn, Dr. Edward Morrisey, to determine the mechanisms by which the observed risk variants alter transcription factor function using in vitro techniques. This application uses genomic approaches to study cardiac transcription factors directly in human subjects with common forms of heart disease. The use of two established cohorts with large sample sizes and quantitative echocardiography will provide the phenotypic data necessary to address our hypotheses definitively, and will capitalize on investments already made in establishing large, well-phenotyped cohorts. By focusing on factors of central importance in animal models that have not been adequately studied in humans, our findings will translate years of basic research into a mechanistic understanding of human cardiac remodeling. Most importantly, we expect to determine and validate genomic predictors of cardiac remodeling that may have clinical applications as tools to predict prognosis and to select high-risk patients for aggressive therapy.
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