Molecular Mechanisms of Rapamycin-induced Reversal of Cardiac Aging

项目摘要/摘要 衰老是心血管疾病的主要风险因素，心血管疾病是美国的主要死亡原因。 即使在没有伴随心血管疾病的个体中，衰老也会导致渐进性结构性和 心脏功能衰退。衰老与舒张期功能下降、心脏收缩功能增加有关 左心室肥厚、心脏储备减少和心肌功能受损的患病率。 舒张期功能下降是心脏老化的一个标志，目前还没有治疗舒张期的方法。 心力衰竭(心力衰竭伴保留射血分数，HFpEF)，这在老年女性中尤其普遍。 尽管心脏老化的表型有很好的特征，但心脏老化的分子机制 还没有得到很好的证实，也没有开发出治疗心脏老化或HFpEF的干预措施。 最近，我们的实验室表明，晚年雷帕霉素治疗10周可以逆转已建立的小鼠 心脏老化，包括舒张期功能障碍的逆转。然而，这种保护作用的机制是 不是很好的特征。这项拟议的研究的目的是确定雷帕霉素如何逆转年龄- 相关的舒张期功能障碍，并确定介导逆转的信号通路。我假设 雷帕霉素通过激活改善的心肌细胞钙离子逆转年龄相关性的舒张期功能障碍 通过抑制TORC1和TORC2信号处理和有益的ECM重塑。至 针对这一假说，我将1)确定雷帕霉素治疗恢复活力的机制 心肌细胞改善老年心脏的舒张功能；2)确定雷帕霉素的作用机制 治疗重塑细胞外基质以改善老年心脏的舒张功能；以及3)确定 TORC1和TORC2信号在雷帕霉素返老还童中的作用及其下游的定义 信号通路。 在指导阶段，我将接受导师的培训，并掌握所建议的 学习。这一奖项将有助于我转变为心脏老化研究的独立研究员。这个 研究结果将引导人们对心脏健康寿命的关键调控因素有基本的了解，并有助于指导未来 雷帕霉素治疗HFpEF的翻译研究，这是一种以前无法治疗的老年病。

Project Summary/Abstract Aging is a dominant risk factor for cardiovascular disease, the leading cause of death in the United States. Even in individuals without concomitant cardiovascular disease, aging results in progressive structural and functional decline of the hearts. Aging is associated with a decline in diastolic function, an increase in the prevalence of left ventricular hypertrophy, reduced cardiac reserve, and impaired myocardial performance. Decline in diastolic function is a hallmark of cardiac aging, and there is presently no treatment for diastolic failure (heart failure with preserved ejection fraction, HFpEF), which is especially prevalent in aged women. Although the phenotypes of cardiac aging are well-characterized, the molecular mechanisms of cardiac aging are not well established and no intervention has been developed to treat cardiac aging or HFpEF. Recently, our lab has shown that late-life rapamycin treatment of 10 weeks can reverse established murine cardiac aging, including a reversal of diastolic dysfunction. However, the mechanism of this protective effect is not well characterized. The objective of the proposed study is to determine how rapamycin reverses age- related diastolic dysfunction and define the signaling pathways that mediate the reversal. I hypothesize that rapamycin reverses age-related diastolic dysfunction by triggering improved cardiomyocyte calcium handling and beneficial ECM remodeling by inhibitions of both TORC1 and TORC2 signaling. To address this hypothesis, I will 1) determine the mechanisms by which rapamycin treatment rejuvenates cardiomyocytes to improve diastolic function in old hearts; 2) determine the mechanisms by which rapamycin treatment remodels extracellular matrix to improve diastolic function in old hearts; and 3) determine the contributions of TORC1 and TORC2 signaling on rapamycin rejuvenating benefits and define the downstream signaling pathways. In the mentored phase, I will receive trainings from my mentors and master the skills required for the proposed study. This award will facilitate my transition into an independent investigator in cardiac aging research. The results of study will lead to fundamental insights into key regulators of cardiac healthspan and help guide future translational studies of rapamycin treatment for HFpEF, a previously untreatable disease of aging.