JAK2条件性基因敲除小鼠中髙糖刺激内皮细胞凋亡与血管内皮功能障碍的研究

项目名称： JAK2条件性基因敲除小鼠中髙糖刺激内皮细胞凋亡与血管内皮功能障碍的研究

项目编号： No.81500637

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 熊飞

作者单位： 华中科技大学

项目金额： 18万元

中文摘要： 内皮细胞(ECs)凋亡引起许多危险因素导致血管内皮功能障碍，血管内皮功能障碍是导致糖尿病心血管并发症的关键因素，但其病理机制至今尚不明了，在糖尿病中，内皮细胞凋亡与血管内皮功能障碍关系仍知之甚少。申请者的前期研究揭示高糖(HG)刺激JAK/STAT信号通路活化，ECs发生凋亡。故申报者提出如下假设：HG引起内皮细胞产生过量ROS诱发氧化应激，激活JAK/STAT信号通路，导致ECs凋亡，进而导致血管内皮功能障碍。为了验证这一假说，拟在原代培养内皮细胞和JAK2条件基因敲除小鼠及JAK2/APOE双基因敲除小鼠，研究HG导致的ECs凋亡及血管内皮功能障碍的关系，阐明HG所致血管内皮损伤的分子机制，研究调控JAK/STAT信号通路对预防和治疗糖尿病诱导的ECs凋亡和内皮功能损伤的可行性。该研究不仅为解析糖尿病血管内皮损伤的分子机制提供新思路，还能为开发糖尿病心血管并发症的治疗策略提供理论基础。

中文关键词： Jak2条件性基因敲除小鼠；JAK/STAT信号通路；分子机制；血管内皮功能障碍；内皮细胞凋亡

英文摘要： Endothelial apoptosis may be a major determinant of endothelial dysfunction. Endothelial dysfunction has long been realized to be a pivotal factor contributing to the pathogenesis of diabetic cardiovascular complications, but the underlying moelcular mechanisms are yet to be fully addressed,the relationship between endothelial apoptosis and dysfunction is not clear. Our preliminary studies now provided evidence supporting that ednothelial cells (ECs) show enhanced JAK/STAT signaling after high glucose stimulation and ECs apoptosis. We therefore hypothesize that hyperglycemic stimulation induce excessive production of reactive oxygen species (ROS) and oxidative stress, which then activate JAK/STAT signaling, predisposing endothelial cells to undergoing apoptosis and functional impairment. To test the above hypothesis, We will use diabetic animals to establish that altered activation of JAK/STAT signaling acts as a key factor for induction of endothelial apoptosis and functional impairment. Then, we will assess the feasibility of blockade of JAK2 signaling for prevention and treatment of diabetic endothelial dysfunction by employing endothelial specific JAK2 and APOE deficient mice. Completion of these studies will not only provide novel insight into the understanding of the mechanisms underlying diabetic endothelial dysfunction, but also have the potential for developing effective therapeutic strategies for prevention and treatment of diabetic cardiovascular complications.

英文关键词： Jak2 conditional knockout miceh;JAK/STAT signal pathway;molecular mechanism;vascular endothelial dysfunction;endothelial cell apoptosis