A long term goal of this proposal is to delineate the mechanisms by which protein surplus cardiomyopathies (PSCs) progress to congestive heart failure. PSCs are an emerging group of cardiomyopathies. Desmin-related myopathy often presents as desmin-related cardiomyopathy (DRC) and exemplifies PSCs. DRC is characterized by aberrant desmin aggregation in muscle cells and this aggregation appears to play a central role in DRC pathogenesis. Notably, similar abnormal desmin aggregates were also observed in human congestive heart failure (CHF) resulting from idiopathic dilated cardiomyopathy, a common heart disease. However, it remains unclear how abnormal desmin aggregation affects cellular functions. The current proposal focuses on the ubiquitin-proteasome system (UPS) mediated protein degradation, a cellular process essential to virtually all aspects of cell function. The central hypothesis is that aberrant desmin aggregation characteristic of DRC impairs proteolytic function of the UPS, representing a nodal pathogenic process in PSCs.
These specific aims will be pursued: (1) To define dynamic modulation of the UPS in a DRC mouse model; if compromised, to further decipher at which step(s) in the UPS cascade the defect(s) resides. This is to test the hypothesis that the UPS is impaired in the progression of DRC and the acquired defect of the UPS pathway resides primarily in the proteasome-mediated protein degradation rather than ubiquitylation. (2) To test a cause-effect link between aberrant desmin aggregation and UPS impairment in intact mice. The underlying hypothesis is that aberrant desmin aggregation instead of disruption of the desmin network impairs the UPS in DRC. (3) To determine whether transactivational activity of beta-catenin is altered in the DRC mouse heart and if so, to test if the alteration can be recapitulated by expression of a DRC-linked desmin mutant or by proteasomal inhibition in cultured heart muscle cells. This is to test the hypothesis that beta-catenin signaling is altered as a result of UPS impairment by aberrant desmin aggregation in cardiac myocytes. Ultimately, this research will help search for new measures to prevent or better treat human CHF.
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