转胶蛋白Transgelin在先天性心脏病相关性肺动脉高压肺血管重构中的作用及机制研究

In our previous research, transgelin was found to be closely related to irreversible pulmonary vascular lesion in pulmonary arterial hypertension associated with congenital heart disease(CHD-PAH). But the role and mechanism of transgelin in pulmonary vascular remodeling of CHD-PAH are not clear yet. In this project, our research hypothesis is that: In CHD-PAH, transgelin may influence the phenotype switch of pulmonary arterial smooth muscle cell (PASMC), which will then contribute to pulmonary vascular remodeling. And in this process, FGF2 signal pathway may be the key pathway that regulates the expression of transgelin and the phenotype switch of PASMC. In this project, shunt flow induced pulmonary arterial hypertension animal model will be used to illuminate the role of transgelin and phenotype switch of PASMC in pulmonary vascular remodeling of CHD-PAH. Cultured PASMC under fluid shear stress stimuli is used to simulate the pathophysiological process of CHD-PAH, so that to confirm the influence of transgelin on the phenotype switch of PASMC. The mechanism of FGF2 signal pathway in regulating the expression of transgelin and phenotype switch of PASMC was deeply explored in animal model and in vitro with pathways interference methods. Our research will provide important scientific basis for clinical evaluation of the reversibility of pulmonary vascular lesion in CHD-PAH.

本课题组前期研究发现，Transgelin与CHD-PAH不可逆性肺血管病变相关。Transgelin在CHD-PAH肺血管重构中的作用和机制还不清楚。本项目的研究假设是：在CHD-PAH中，Transgelin可能通过影响肺动脉平滑肌细胞（PASMC）表型转化而促进肺血管重构，且FGF2信号通路可能是调控Transgelin表达和PASMC表型转化，进而影响肺血管重构的机制通路。本研究拟以分流型肺动脉高压为模型，明确Transgelin和PASMC表型转化在CHD-PAH肺血管重构中的作用；以体外流体剪应力刺激PASMC模拟CHD-PAH病理环境，明确Transgelin对PASMC表型转化的影响；以动物模型和体外通路干预相结合的方法，深入探讨FGF2信号通路调控Transgelin表达和PASMC表型转化的机制，从而为临床评估CHD-PAH肺血管病变的可逆性提供重要科学依据。

先天性心脏病相关性肺动脉高压(CHD-PAH)的可逆性研究是世界前沿热点课题，也是困惑临床工作的难点问题。Transgelin是一种肌动蛋白结合蛋白，调节肺动脉平滑肌细胞(PASMC)的功能。为此，本研究旨在探讨transgelin在CHD-PAH发病机制中的作用和机制。材料与方法:采用免疫组化方法检测肺组织中Transgelin的表达。通过体外增殖、迁移和凋亡实验探讨transgelin在人PASMCs (HPASMCs)中的生物学功能和肺血管重构的分子机制。结果:Transgelin在CHD-PAH患者和mct - av诱导PAH大鼠肺组织中均过表达。TGF-β1和transgelin在组织和亚细胞水平上均与肺血管重构的病理改变相关。敲除transgelin基因可通过抑制TGF-β1信号通路降低HPASMCs的增殖、迁移和凋亡抵抗。结论:Transgelin可能通过TGF-β1信号通路导致人PASMC功能紊乱，transgelin可能成为逆转或者阻断CHD-PAH肺血管重构的关键靶标。