DPP4/HIF-1α介导循环中sFlt-1异常在肝肺综合症重症化启动中的作用和机制研究

肝肺综合症（HPS）机制复杂，防治困难；在其“病情进展早期阻断其重症化启动”有望成为防治研究新思路。既往报道肝硬化以及HPS患者循环中PIGF/VEGF等显著增高，是形成病理性血管新生（PPA）的重要因素，但仅少数进展为重症，提示另有关键机制。进一步预实验发现“循环中sFlt-1异常可能是HPS重症化启动的早期关键事件”，亟待深入验证。结合最新文献报道，本课题提出“慢性肝病→胆管上皮细胞内DPP4激活→HIF-1α→抑制sFlt-1表达致循环中低水平→拮抗PIGF/VEGF血管新生效应减弱→PPA形成→重症化”假说。拟利用大鼠HPS在体和离体模型以及HPS患者组织，采用转基因、光遗传学等多种分子生物学技术，阐明循环中sFlt-1异常的调控机制，验证“抑制DPP4/HIF-1α调控sFlt-1水平”作为阻断HPS重症化启动的更优干预靶点的可行性，并为获得更佳保护的防治新策略奠定一定理论基础。

The mechanism of hepatopulmonary syndrome (HPS) is complex and difficult to prevent and treat.It has become a new idea to block the initiation of severe disease in the early stage of disease progression.Previous studies reported that PIGF/VEGF in the circulation of cirrhosis or HPS patients are significantly increased, which is an important factor in the formation of pathological angiogenesis (PPA). However, only a small part of them have developed into severe phase, suggesting there exitsted other more important mechanisms. Further preliminary experiments found that "the abnormality of sFlt-1 in circulation may be an early key event for the initiation of severe phase of HPS", which urgently needed in-depth verification. Combined with the latest literature reports, this project proposed the hypothesis of "chronic liver disease → DPP4 activation in bile duct epithelial cells →HIF-1α pathway → inhibition of sFlt-1 expression resulting in low circulating level → antagonism of PIGF/VEGF with reduced angiogenic effect →PPA formation →HPS aggravation". Using HPS in vivo and in vitro of rats model, using genetically modified, light and other molecular biology techniques, clarify cycle regulatory mechanism of abnormal sFlt - 1, verify that " inhibiting DPP4/ hif-1 and regulating sFlt-1 level in blood circulation " as a block of HPS intensive launch better feasibility of intervention targets, and to obtain a better protection of a certain foundation for prevention and control of the new strategy.