Molecular Mechanisms of Rapamycin - Induced Reversal of Cardiac Aging

项目总结/摘要 老龄化是心血管疾病的主要危险因素，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，衰老也会导致进行性结构性和 心脏功能衰退。衰老与舒张功能的下降、心脏舒张功能的增加有关。 左心室肥大、心脏储备降低和心肌功能受损的患病率。 舒张功能下降是心脏老化的标志，目前还没有舒张功能下降的治疗方法。 心力衰竭（射血分数保留的心力衰竭，HFpEF），在老年女性中尤其普遍。 虽然心脏衰老的表型特征很好，但心脏衰老的分子机制 尚未得到充分证实，也没有开发出治疗心脏衰老或HFpEF的干预措施。 最近，我们的实验室已经表明，晚期雷帕霉素治疗10周可以逆转已建立的小鼠 心脏老化，包括舒张功能障碍的逆转。然而，这种保护作用的机制是 没有很好地描述。这项研究的目的是确定雷帕霉素是如何逆转衰老的。 相关的舒张功能障碍，并确定介导逆转的信号通路。我假设 雷帕霉素通过提高心肌细胞钙离子水平逆转年龄相关性舒张功能障碍 通过抑制TORC 1和TORC 2信号传导来处理和有益的ECM重塑。到 解决这个假设，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舒张功能; 2）确定雷帕霉素 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 TORC 1和TORC 2信号传导对雷帕霉素再生益处的贡献，并定义了下游 信号通路 在指导阶段，我将接受导师的培训，并掌握拟议职位所需的技能 study.这个奖项将促进我转变为心脏衰老研究的独立调查员。的 研究结果将导致对心脏健康的关键调节因子的基本见解，并有助于指导未来的研究。 雷帕霉素治疗HFpEF的转化研究，HFpEF是一种以前无法治疗的衰老疾病。

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.