GDF11-ALK7/TβR-SIRT1调控血管细胞异质性转换在胸主动脉夹层形成中的作用机制研究

血管平滑肌细胞（SMC）表型转换和巨噬细胞（MՓ）极化导致主动脉结构和功能异常，其分子机制复杂，一直是该研究领域热点。近年来发现GDF11是调控心血管组织结构和功能的关键分子，但其主动脉效应未见报道。我们首次证实：外源性补充GDF11可明显抑制胸主动脉夹层形成，但具体机制不清。结合我们前期系列研究和文献报道：SIRT1作为主动脉血管重构进程中的关键效应靶点，是介导SMC表型转换和MՓ极化的重要内源性分子。其它组织研究发现SIRT1可能位于GDF11调控下游。综上提出如下科学假说：GDF11通过经典TβR受体或特异性ALK7受体依赖途径，激活SIRT1关键信号，介导调控SMC表型转换和MՓ极化，从而抑制胸主动脉夹层形成。本项目拟基于已建立的临床数据库，采用腺相关病毒、基因敲除、Transwell等技术，通过细胞、动物、临床标本多层次研究阐明上述科学假说，为胸主动脉夹层防治寻找新的干预靶点。

Vascular smooth muscle cell (SMC) phenotypic transformation and macrophage (MՓ) polarization lead to abnormal aortic structure and function, the mechanism of which is complex and has been a hot issue. GDF11 is involved in the regulation of cardiovascular structure and function, but its aortic effects have not been reported. We innovatively found that GDF11 was a powerful endogenous factor protecting against thoracic aortic dissection, but the underlying mechanism remained to be elucidated. Our previous studies and literature review demonstrate that SIRT1 is a critical target in aortic remodeling, mediating the SMC phenotypic transformation and MՓ polarization. Additionally, SIRT1 may be located in the downstream of GDF11. Therefore, we speculate that GDF11 activates SIRT1 signaling in the TβR/ALK7 receptor-dependent manner, retarding the formation of thoracic aortic dissection via regulating SMC phenotypic transformation and MՓ polarization. This project aims to prove the hypothesis in cellular, animal and clinical level by using the biobank, adeno-associated viruses, gene knockout mice, Transwell and other technologies. In this way, we may provide novel interventional targets for the prevention and treatment of thoracic aortic dissection.