Activation of the mTORC1 complex is a critical step in the progression of cardiac disease after myocardial infarction and pressure overload induced hypertrophy. This fact has spurred interest for ways to therapeutic target the mTORC1 complex in the heart. However, no drugs are currently available that specifically target mTORC1 in cardiomyocytes highlighting the need for the development of new therapeutic regimes. This proposal will inhibit mTORC1 through a novel molecular strategy involving PRAS40, an endogenous mTORC1 inhibitor and substrate. PRAS40 has been identified in the last years as a powerful tool to inhibit cellular growth in cancer cells. A unique molecular feature of PRAS40 is to inhibit mTORC1 and simultaneously increase mTORC2 activation, which increase cellular survival via increased AKT activation. Judicious enhancement of PRAS40 expression will inhibit pathological growth and senescence on the one hand and improve survival on the other hand. Accomplishing the stated aims of this proposal will provide a first comprehensive characterization of PRAS40 in cardiac biology. The innovation of this proposal is based on the first characterization of PRAS40 in the cardiac context and the unique molecular profile of PRAS40. The short- term goal is to delineate the critical importance of PRAS40 in the heart and demonstrate the efficiency of PRAS40 interventional approaches to inhibit pathological growth, blunt cardiac senescence and improve insulin signaling.
Specific aims are: 1) Pathological cardiac growth and senescence are inhibited by PRAS40, 2) cell survival and insulin signaling are improved by PRAS40 and 3) that mTORC1 inhibition together with mTORC2 activation by PRAS40 is protective against pathological damage. The significance of these studies is to define ways to blunt hyperactivation of mTORC1 in cardiac diseases with the goal to delineate new therapeutic ways to target mTORC1 in the heart. Collectively, the studies in this proposal will pave the way for interventional approaches to regulate PRAS40 activity in service to block pathological growth and senescence and improving AKT dependent signaling.
Heart disease, especially heart failure, is a major public health issue in the United States placing a considerable burden upon our health care system. Despite recent progress in understanding pathophysiology, heart failure still carries a 5-year mortality that rivals most cancers. This proposal focuses upon a novel fundamental molecular mechanism involving inhibition of pathological growth and blunting of senescence together with improving survival to maintain cardiac structure and function after myocardial infarction or pressure overload.
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