Summary Pressure overload induced cardiac hypertrophy, such as that caused by chronic hypertension, is a key risk factor for heart failure. Accumulating evidence from studies in patients and animal models suggests that cardiac hypertrophy induced by the chronic pressure overload is not a compensatory but rather is a maladaptive process. Thus, modulation of pathological myocardial hypertrophy is increasingly recognized as a potentially promising approach in the prevention of development of heart failure. Despite intensive research efforts over several decades, the molecular mechanisms of hypertrophic heart failure are not fully understood. Our recent study found that the valosin-containing protein (VCP), a protein which is previously uncharacterized in the heart, represents a mediator of cardioprotection that is directly relevant to the condition of cardiac hypertrophy and dysfunction induced by hypertension in patients. The originality of this proposal is based on our preliminary findings that VCP expression is significantly down-regulated in the pressure overloaded hearts in variant animal models. We also found that cardiac specific overexpression of VCP in a transgenic mouse significantly attenuates the pressure overload induced cardiac hypertrophy and dysfunction, while impaired VCP accelerates cardiac dysfunction under pressure overload and also hastens age related cardiomyopathy. We also found that VCP presents a dual regulatory effect on the signaling of mechanistic target of rapamycin (mTOR) in the heart. As supported by the Preliminary Data, our overall hypothesis is that VCP is a novel mediator that protects heart against the pressure overload-induced cardiac hypertrophy and dysfunction by regulating the survival and growth of cardiomyocytes through selectively activating mTORC2 but inhibiting mTORC1 signaling under cardiac stress. Thus, in this proposal, we will elucidate further the physiological relevance and the underlying mechanisms of VCP in the heart at baseline and under pressure overload through two Specific Aims. Our first Aim is to determine the physiological relevance of VCP to the cardiac growth and function during aging and under pressure overload. We will test our hypothesis that an insufficiency of VCP is responsible for the pathogenesis of cardiac hypertrophy and dysfunction during aging and under pressure overload of heart, and an overexpression VCP will provide protection against the cardiac deterioration under these conditions. Our second Aim is to elucidate the molecular mechanisms of cardiac protection conferred by VCP. We will test our hypothesis that VCP acts as a unique dual regulator for mTOR complexes by selectively activating the survival complex mTORC2 but inhibiting the growth-promoting complex mTORC1 under the pathological stress. We also hypothesize that this selective effect of VCP depends on its N-terminal regulatory domain. Based on our extensive preliminary data and previous publications, we strongly b...