T-cadherin-脂联素及相关外泌体调控在血管内皮损伤修复中的作用机制及潜在药物新靶点研究

申请人前期研究发现T-cadherin可能成为直接作用于血管内皮细胞，治疗动脉粥样硬化、冠脉再狭窄的新药靶点。因此，本研究拟从细胞、动物和人体水平开展系统研究。首先在细胞水平和动物模型中，证明在各种环境或刺激条件下，血管内皮细胞中或循环中T-cadherin、脂联素、外泌体miRNA类型及水平的变化，并阐明T-cadherin作用的下游通路。然后，通过构建细胞shRNA调控模型和T-cadherinKO小鼠模型，下调血管内皮细胞T-cadherin表达，评估T-cadherin对内皮细胞损伤修复的调控能力；最后，在课题组前期建立的冠心病支架植入术后和颈动脉狭窄症的两个患者队列中，分析CDH13基因多态性，血浆中脂联素、T-cadherin、外泌体、外泌体miRNA，及病变血管T-cadherin表达水平相互间的联系，评估T-cadherin作为血管损伤修复药物新靶点的潜力。

Vascular diseases have long been at the top of the total cause of death for residents in China. At present, there are no drugs that have a clear mechanism of action and directly affect blood vessels to repair vascular injuries. Our previous research found that the T-cadherin encoding gene CDH13 gene polymorphism was significantly associated with the risk of re-implantation of the stent after coronary heart disease. T-cadherin is a receptor for adiponectin and mediates the formation of exosomes. We found that T-cad might complete repair of vascular endothelial injury by regulating the formation and release of exosomes, which might become a new drug target that directly acts on vascular endothelial cells to treat atherosclerosis and coronary restenosis. Therefore, this study intends to carry out systematic research at the level of cells, animals, and humans. First, at the cell and animal models, it is demonstrated that under various environmental or stimulating conditions, T-cad levels varies in vascular endothelial cells and in circulation, and the level of miRNA and other substances in exosomes change. Then, T-cad expression level of vascular endothelial cells is downregulated by siRNA (Lentivirus) at the cell level and T-cadherin KO mouse model at the animal level, and we observe the effects on vascular endothelial cell function, exosomes, miRNA, and elucidate the downstream pathway of T-cad function. Finally, in the two cohorts of coronary artery disease stent implantation and Carotid stenosis disease established earlier in the research group, analyze the CDH13 gene polymorphism, serum adiponectin, the Correlation among T-cad, exosomes, miRNA levels, and T-cad expression levels in injured vessels, assessing the potential of T-cadherin as a new drug target from animal and human levels.