Cardioprotection by optimizing mTOR activity

描述(由申请人提供)：mTORC1复合体的激活是心肌梗死和压力超负荷引起的肥厚后心脏病进展的关键步骤。这一事实激发了人们对以心脏中mTORC1复合体为靶点的治疗方法的兴趣。然而，目前还没有专门针对心肌细胞mTORC1的药物，这突显了开发新的治疗方案的必要性。这一建议将通过一种新的分子策略来抑制mTORC1，该策略涉及内源性mTORC1抑制剂和底物PRAS40。在过去的几年里，PRAS40被确定为一种有效的工具来抑制癌细胞中的细胞生长。PRAS40的一个独特的分子特征是抑制mTORC1，同时增加mTORC2的激活，从而通过增加AKT的激活来提高细胞存活率。适当增强PRAS40的表达，一方面可以抑制病理性生长和衰老，另一方面可以提高存活率。实现这项提案的既定目标将首次在心脏生物学中提供PRAS40的全面特征。这一建议的创新之处在于首次在心脏环境中描述了PRAS40的特征以及PRAS40独特的分子特征。短期目标是阐明PRAS40在心脏中的关键重要性，并证明PRAS40干预方法在抑制病理性生长、减缓心脏衰老和改善胰岛素信号方面的有效性。其具体目的是：1)PRAS40抑制病理性心脏生长和衰老；2)PRAS40改善细胞存活和胰岛素信号转导；3)PRAS40抑制mTORC1和激活mTORC2对病理损伤具有保护作用。这些研究的意义是确定在心脏病中钝化mTORC1过度激活的方法，目标是描绘针对心脏中mTORC1的新的治疗方法。总之，本提案中的研究将为干预方法调节PRAS40活性、阻止病理性生长和衰老以及改善AKT依赖的信号通路铺平道路。

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.