Smad4调控网络在慢性血栓栓塞性肺动脉高压血管重塑中的机制及匹诺塞林干预作用研究

慢性血栓栓塞性肺动脉高压(CTEPH)是一种罕见却十分严重的疾病，缺少治疗药物，且其肺血管重塑导致血栓形成机化的根本原因不清，阻碍治疗手段发展。前期研究发现Smad蛋白以Smad4为核心网络式调控血管重塑，参与血栓形成和机化，干预Smad4核转位可以减少重塑和血栓的发生。但Smad4在CTEPH发生过程中上下游信号分子及靶基因调控机制并不清楚。基于此，本课题将以Smad4为切入点，利用体内外实验结合生物信息学、分子对接等手段，探讨CTEPH血管重塑诱导血栓形成机化过程中，Smad4的调控网络、协同转录因子及其靶基因，明确Smad4调控网络-靶基因-血管重塑-血栓机化信号轴在CTEPH中的作用。利用黄酮类化合物匹诺塞林进行干预，确证Smad4是CTEPH防治的潜在药物靶点。本项目将有助于深入了解CTEPH的病理生理机制，为CTEPH治疗方法、药物靶点发现提供新的思路，具有重要科学意义。

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but serious disease, and it lacks treatment drugs. The underlying causes of thrombus organization induced by vascular remodeling have not been clearly explained. Our previous work have shown that several subtypes of Smad proteins taking Smad4 as the center to be involved in pulmonary vascular remodeling in rats with pulmonary hypertension. In the case of vascular remodeling, thrombosis and organization are aggravated in pulmonary arteries, which could be reduced by intervention of Smad4 nuclear translocation. However, it is not clear the up- and down-stream signaling pathways and target genes of Smad4. Based on this, this study will start with Smad4 to analyze its role and the regulatory network in the development of CTEPH, especially in the vascular remodeling, its co-transcription factors and the target genes. The interaction between blood vessels and thrombus and the molecular mechanism that interacts with the thrombus and the regulatory genes involved in it will be studied. The project will be developed through animal, ex vivo organs and cells experiments combined with bioinformatics and molecular docking. The study will elucidate the influence of Smad4 regulatory network-target gene-pulmonary artery remodeling-thrombus signaling pathway in CTEPH. Furthermore, the intervention of a kind of flavonoids, Pinocembrin, is used to confirm the possibility of Smad4 as a drug target in the prevention and treatment of CTEPH. This project will provide new ideas for the pathogenesis, treatment methods and new drug targets discovery of CTEPH.