Heart failure has become the most common reason for adult hospitalization in the industrialized world. Basic research has shown that pathologic stresses promote heart failure via activation of cardiac transcription factors (TFs). These TFs interact with each other and with co-activators to form """"""""transcriptional modules"""""""" (TMs) that alter cardiac gene expression to cause myocyte hypertrophy and failure. In light of their critical role in heart failure pathogenesis, TMs have been the subject of intensive research in animal models over the past decade. By contrast, the role of TMs in human heart failure remains largely unexplored because of limited methods for studying TFs in human subjects. We have piloted computational approaches that enable assessment of TF function in the failing human heart by integrating cardiac gene expression data from microarray experiments with readily available genome sequence data. However, these do not sufficiently address the complexity of the underlying biology, and more rigorous methods are needed. The purpose of this exploratory/developmental research proposal is to determine transcriptional modules (TMs) associated with human heart failure using a refined computational approach and to experimentally validate the most promising TM using standard in vitro techniques. We will develop novel integrative approaches to determine TMs associated with human heart failure and apply them to the Penn Cohort, the largest study of human cardiac gene expression in the published literature. These approaches integrate whole genome expression data with data from promoter sequences, TF binding motifs, and cross-species sequence alignments. Our most promising newly identified heart failure TM will be validated experimentally using in vitro reporter gene assays in cardiac myocytes. This interdisciplinary proposal will build on existing collaboration between a clinical investigator, a computational biologist, a biostatistician, and a molecular biologist. Our research will determine TMs directly relevant to the pathogenesis of human heart failure. In doing so, we will extend an important body of work in animal models to the arena of clinical investigation. The specific heart failure TMs we identify will become the focus of future research performed by our own group and by others. These studies may ultimately lead to new drugs that target transcriptional mechanisms of hypertrophy, a central feature of heart failure that is not directly targeted by any current therapy. Lastly, the computational methods we develop should have broad application to study other human diseases. Heart failure has become the most common reason for adult hospitalization in the industrialized world. Research performed over the past decade has determined that cardiac transcription factors play a crucial role in the pathogenesis of heart failure, but these findings have not been extended to human subjects. This proposal will develop and apply novel genomic approaches to study the role of cardiac transcription factors in human subjects with advanced heart failure.
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