mTORC1在重度二尖瓣反流所致左室心肌重构中的作用研究

Mitral regurgitation is the most frequent form of valvular heart diseases. The natural history of severe MR is a gradual progressive left ventricular remodeling, resulting in heart failure. Severe MR with heart failure can present a difficult management dilemma; corrective valve surgery is not recommended, and medical therapy is ineffective. In particular, Mechanism of left ventricular remodeling in MR is still unclear. Our research group has generated severe MR mouse model, which could mimic human natural history of severe MR. Regarding molecular mechanism, we have screened relevant hypertrophy pathways, and found S6 Ribosomal protein and 4EBP1 activated in MR hearts, which is downstream of mTORC1. This study will focus on mTORC1, to explore related upstreams in severe MR hearts, and plan to use mTOR inhibitor---rapamycin to confirm the role of mTORC1 in left ventricular remodeling in severe MR. This study will play an important role in explaining the mechanism of left ventricular remodeling in severe MR, and will be beneficial to prevent heart failure in these patients.

二尖瓣反流(mitral regurgitation, MR)是最常见的心脏瓣膜病。重度MR的自然病程为左室重构致不可逆心衰。重度MR合并心衰的患者仍面临治疗困境：既不推荐进行手术修补或置换，也无有效药物治疗。究其根本，目前对于MR导致左室心肌重构的确切机制尚不清楚。申请人前期成功构建了重度MR小鼠模型，并验证该模型可模拟人体重度MR致左室重构及心衰的临床病程。在分子机制方面，申请人前期筛选相关分子通路，发现S6核糖体蛋白与4EBP1活化上调，此为mTORC1(mammalian target of rapamycin complex 1)的下游因子。本研究将以mTORC1为基点，一方面探索在重度MR中表达的上游通路；另一方面通过应用mTORC1抑制剂雷帕霉素进一步验证mTORC1在重度MR左室重构中的作用。本研究对探索重度MR致左室重构的机制具有重要意义，并有望为临床上预防心衰提供思路。

目前对于重度二尖瓣反流（mitral regurgitation, MR）如何导致心肌重构至不可逆心肌损伤的机制仍不清楚，对重度MR合并心衰患者的治疗仍处于困境。本课题首先构建了重度MR小鼠模型，监测验证左室心肌离心性肥大与心衰；在蛋白水平检测到mTORC1活化，追踪上游分子P13K-Akt通路激活；应用mTORC1抑制剂雷帕霉素后心肌重构程度减轻。本课题发现并验证了mTORC1在重度MR左室心肌重构中的作用，有益于为临床上针对重度MR患者预防心衰提供靶点与思路。