Cardioprotection by optimizing mTOR activity

描述（由申请方提供）：mTORC 1复合物的激活是心肌梗死和压力超负荷诱导肥大后心脏疾病进展的关键步骤。这一事实激发了人们对治疗心脏中mTORC1复合物的方法的兴趣。然而，目前没有药物可以特异性靶向心肌细胞中的mTORC 1，这突出了开发新治疗方案的需要。该提议将通过涉及PRAS 40（内源性mTORC1抑制剂和底物）的新型分子策略来抑制mTORC1。PRAS 40在过去几年中已被确定为抑制癌细胞中细胞生长的有力工具。PRAS 40的独特分子特征是抑制mTORC 1并同时增加mTORC 2活化，这通过增加AKT活化来增加细胞存活。明智地增强PRAS 40表达一方面将抑制病理性生长和衰老，另一方面将改善存活。实现该提案的既定目标将提供心脏生物学中PRAS 40的第一个全面表征。该提案的创新是基于心脏背景下PRAS 40的首次表征和PRAS 40的独特分子谱。短期目标是描述PRAS 40在心脏中的至关重要性，并证明PRAS 40介入方法抑制病理性生长、减缓心脏衰老和改善胰岛素信号传导的效率。具体目标是：1）病理性心脏生长和衰老被PRAS 40抑制，2）细胞存活和胰岛素信号传导被PRAS 40改善，和3）mT0RC 1抑制与mT0RC 2激活一起被PRAS 40保护免于病理性损伤。这些研究的意义在于确定在心脏疾病中钝化mTORC1过度激活的方法，目的是描绘靶向心脏中mTORC1的新治疗方法。总的来说，本提案中的研究将为调节PRAS 40活性的干预方法铺平道路，以阻断病理性生长和衰老并改善AKT依赖性信号传导。

DESCRIPTION (provided by applicant): 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.