低氧诱导的血小板源性PDGFA促进胆道闭锁中肝脏病理性微血管新生的机制研究

病理性血管新生是加重肝胆疾病纤维化的关键诱因，然而其对胆道闭锁（BA）的病理学意义及防治尚缺乏深入研究。我们以BA患儿肝脏处于低氧微环境为切入点，预实验结果发现BA中血小板过度活化及其PDGFA表达升高，并可促进微血管新生；继而蛋白质组学乳酸化修饰分析及细胞学实验结果显示，BA血小板上与激活相关的膜蛋白乳酸化修饰水平增加。据此我们提出BA中血管病理学特征形成的新机制：低氧可致血小板转向糖酵解，细胞内乳酸蓄积，诱导靶蛋白乳酸化修饰增强而激活血小板，增加其分泌PDGFA进而促进BA中肝脏血管新生。本课题拟通过BA模型和血小板条件敲除PDGFA小鼠，深入探讨低氧诱导血小板乳酸化修饰改变而激活的具体机制，进一步验证分泌的血小板源PDGFA具有促进BA疾病模型中血管新生的新功能，为阐明BA血管病理学特征形成提供新的理论依据，为BA的早期诊断和靶向治疗提供新的思路。

Pathological angiogenesis is the key cause of aggravating hepatobiliary fibrosis, but its pathological significance and prevention of biliary atresia (BA) still lack in-depth studies. Taken the liver of BA in a hypoxic microenvironment as the starting point，we have recently observed that overactivated platelets increase the expression of PDGFA and promote the pathological micro-angiogenesis. Further proteomics analysis of lactylation and cytological experiment results show that the platelets activation-related membrane protein increase the modification of lactylation in BA. Based on this, we propose a new mechanism of BA vascular pathology: Platelet will turn to glycolysis in hypoxia, leading to the accumulation of lactate, that could induce platelets activation due to the enhanced lactylation of platelet-target, thereby increasing its secretion of PDGFA to promote liver angiogenesis in BA. Through BA mouse model or KO-PDGFA gene mice of conditional-platelets, this project intends to explore the specific regulation mechanism of platelet activation induced by hypoxia-induced lactylation, and further verify the secreted platelet-derived PDGFA has a new function to promote angiogenesis in BA model. Thus, this project provides a new theory for pathological neovascularization in biliary atresia, which may develop into a new diagnostic and therapeutic idea for biliary atresia.