The ubiquitin proteasome system (UPS) is responsible for the degradation of most proteins in the cell. By clearing abnormal proteins and removing normal proteins that are no longer needed, UPS-mediated proteolysis plays an extremely important role in both quality control of the cell and regulation of the intracellular homeostasis, thereby touching virtually every corner of the cell. Recent studies have revealed that UPS proteolytic function in the heart can be severely impaired by abnormal protein aggregation which is often observed in failing human hearts, suggesting that UPS dysfunction may play an extremely important role in the progression of congestive heart failure (CHF), a clinical syndrome that affects the health and life of millions of Americans. Therefore, a potential new therapeutic strategy is to normalize UPS function in the heart with CHF. In order to do so, the mechanisms that regulate UPS function must first be elucidated. A long term goal of this proposal is to delineate the molecular mechanisms that regulate protein turnover in mammalian hearts by the UPS and provide molecular biology basis for harnessing UPS proteolytic function to treat CHF. A recently discovered protein complex, the COP9 signalosome (CSN) consisting of 8 unique protein subunits (CSN1 approximately CSN8), is evolutionary conserved throughout the eukaryotes. Studies from lower organisms and cultured mammalian cells have shown that CSN plays important roles in many basic cellular processes including regulating the activity of the UPS. This study will test a central hypothesis that CSN cooperates with cullin-based ubiquitin E3 ligases in destruction of regulatory proteins while it suppresses the degradation of abnormal proteins by the proteasome; therefore, it is required for heart muscle cell survival, postnatal cardiac development, and cardiac function. Through conditional gene targeting, a CSN hypomorphic mouse strain has been generated and the heart muscle cells restricted knockout of a CSN gene at the neonatal stage has also been achieved. The impact of CSN loss-of-function or reduced function in the heart on cardiac structure and function and its modulation of the UPS function in the heart will then be defined. This will provide important insights into the function of CSN in the heart and CSN-dependent regulation of UPS functions in the heart. Ultimately, this will help search for new measures to prevent and/or more effectively treat human CHF. ? ? ?
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