Alternative splicing is an important mechanism by which the functions of genes are regulated in response to environmental cues. Regulated alternative splicing of ion channels, structural proteins, apoptosis regulators, and transcription factors is known to occur in heart failure. Thus, regulated splicing has broad potential impact on heart function. However, only a handful of regulated splicing events have been identified, and very likely the vast majority remain unstudied in heart failure. Recent technological developments have made genome-wide studies of alternative splicing feasible. In this proposal, we use a splice-sensitive microarray to perform a genome-wide screen for alternative splicing that is regulated in heart failure. We take advantage of two large collections of failing and non-failing hearts to perform a suitably powered microarray study, followed by a validation study in independent biological samples. These studies will be the first to systematically investigate alternative splicing in human heart failure, and among the first to examine regulation of splicing on a genome- wide level in human disease. We recognize that these aims are descriptive. However, they provide the material that will fuel future hypothesis driven research on specific alternative splicing events that are functionally important in heart failure. Thus, the genome-wide identification of alternative splice products that are differentially expressed in heart failure is both novel and high impact. Heart failure is a leading cause of death in developed countries. Changes in gene expression contribute to the development and progression of heart failure. We have not yet described all of the gene expression changes that happen in heart failure. Some of these changes are due to differences in how a protein is stitched together from genetic information (""""""""alternative splicing""""""""). New technology now enables us to measure all known alternative splice variants. We will apply this technology to better understand gene expression changes in heart failure. This understanding will lead to new hypotheses about how heart failure develops and about how we might improve its treatment.
Heart failure is a leading cause of death in developed countries. Changes in gene expression contribute to the development and progression of heart failure. We have not yet described all of the gene expression changes that happen in heart failure. Some of these changes are due to differences in how a protein is stitched together from genetic information (?alternative splicing?). New technology now enables us to measure all known alternative splice variants. We will apply this technology to better understand gene expression changes in heart failure. This understanding will lead to new hypotheses about how heart failure develops and about how we might improve its treatment.
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