孤核受体Nur77对血栓形成的保护作用及机制研究

Thrombosis is the important cause of cadivascular disease.Thrombomodulin(TM), as a critical molecular in APC anticoagulation pathaway, is the most relevant with thrombosis. In the preliminary experiment, we found that Nur77 increase thrombomodulin mRNA and protein expression dramaticly in Human Umbilical Vein Endothelial Cells(HUVEC).And the APC(activitied proteinC)generation capacity is also elevated in a dose dependent manner. In the arota of Nur77 knockout mice, TM expression is degreased.When over expression Nur77 in mice, thrombomodulin visibly increased in the liver and appeard to localize predominantly to the hepatic sinusoidal cells. And the time to occlusive thrombosis is prolonged.These data indicate that Nur77 regulated Thrombomodulin and involved in anticoagulation pathaway to mediate thrombosis. Therefore, we constuct a thrombosis model using Nur77 knockout mice to investigate the incidence of thrombosis and the severity regulated by Nur77 and TM. based on the HUVEC, we also investigate the mechanism in regulatingTM.Furthermore We analysis the relevance between coagulation indicator of patients and Nur77.This project will give more evidence and supply a new therapy to thrombosis disease.

血栓栓塞是心血管疾病死亡的重要原因。血栓调节蛋白（TM），是机体抗凝APC通路的重要调控分子，与血栓的发生密切相关。前期实验研究发现，孤核受体Nur77能显著提高血管内皮细胞中TM基因及蛋白表达水平，并且能明显提高活化的APC产生的能力，并且这种增高是剂量依赖性的。Nur77基因缺失小鼠血管组织中TM表达明显下调。在小鼠中过表达Nur77，小鼠肝脏中TM表达明显增强，颈动脉血栓模型中血管闭塞时间延长，提示Nur77可能通过调控血栓调节蛋白参与机体抗凝血反应及血栓形成。因此，本实验利用Nur77基因缺失小鼠建立血栓模型，分析血栓发生率和严重程度与Nur77和TM的相关性，并且在细胞实验中探求其调控机制，通过分析血栓病人凝血功能指标与Nur77基因表达的相关性，为预防性及进展中的血栓疾病的治疗提供一种新的治疗方式。

血栓栓塞是心血管疾病死亡的重要原因。血栓调节蛋白（TM），是机体抗凝APC通路的重要调控分子，与血栓的发生密切相关。实验研究发现，孤核受体Nur77能显著提高血管内皮细胞中TM基因及蛋白表达水平，并且能明显提高活化的APC产生的能力，并且这种增高是剂量依赖性的。Nur77的激动剂6MP同样在时间和剂量上都显著提高了TM的表达。在血管内皮细胞生长因子（VEGF）的作用下，Nur77参与调控TM的表达。在孤核受体Nur77基因缺失小鼠中建立血栓模型，分析血栓发生率和严重程度与Nur77和TM的相关性，明确Nur77基因缺失小鼠血栓的发生率及严重程度较野生型小鼠更加严重，从而阐明Nur77对血栓形成的保护作用。本项目将为预防性及进展中的血栓疾病的治疗提供一种新的治疗方式。