Defining Pathways from Gene Mutation to Heart Failure

Harvard Medical School, Boston MA

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Abstract

DESCRIPTION (provided by applicant): There are multiple pathways leading to heart failure, the leading cause of death in man. Human dilated cardiomyopathy (DCM) mutations occur in genes encoding proteins with contractile functions, in proteins involved in force transmission, in proteins of the cytoskeleton, in one nuclear membrane protein, in proteins involved in Ca2+ homeostasis and in a protein involved in transcriptional regulation. These data clearly indicate that definition of all genetic causes of human DCM while still an informative approach for identifying the inciting molecular trigger for remodeling and heart failure will be very laborious. Another approach for addressing this problem is to define the pathways triggered by distinct gene mutations. This approach has several advantages. First information about these signaling pathways has the potential for defining nodal points that may be activated in several DCM genes and non-genetic causes of heart failure. Second, understanding components of these pathways should provide mechanistic insights into ventricular remodeling that may suggest novel therapeutic approaches to attenuate progression to heart failure. Finally, definition of components of these pathways should provide a wealth of candidate disease genes that may also be primary causes of ventricular remodeling and heart failure. While recognizing there are likely multiple pathways leading from a DCM gene mutation to ventricular remodeling and heart failure, we propose to study two: the pathway activated by mutation of a transcription co-factor Eya4 and the pathway activated by a dominant phospholamban (PLN) mutation. The Eya4 disease gene was selected to allow study of transcriptional signals that remodel the heart. The PLN mutation was selected to allow study of how disturbed calcium cycling, a fundamental process in cardiac physiology, causes heart failure. The pathways triggered by these two human DCM genes will be explored through specific aims that will: 1) Characterize cardiac pathophysiology in Eya4-deficient (Eya4+/-) mice. 2) Define the downstream target genes regulated by Eya4 in the heart. 3) Assess which Eya4-responsive genes contribute to DCM. 4) Characterize the histopathology of PLN R9C-induced ventricular remodeling and assess reversibility. 5) Define changes in transcriptome and proteome in PLN R9C hearts. 6) Assess the primacy of PLN R9C-altered proteins in DCM and heart failure.