TLR4参与糖尿病动脉粥样硬化的分子机制研究

项目名称： TLR4参与糖尿病动脉粥样硬化的分子机制研究

项目编号： No.81471051

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 齐若梅

作者单位： 北京医院

项目金额： 80万元

中文摘要： 糖尿病时出现TLR4增高、血小板功能亢进、内皮细胞功能损伤等现象，然而，TLR4表达增加对血小板功能、内皮细胞功能以及对糖尿病动脉粥样硬化的影响尚不清楚。我们在前期工作中发现高糖增加TLR4在血小板和内皮细胞表达，还观察到高糖刺激血小板炎症蛋白释放、内皮细胞粘附蛋白表达，而抑制PAF受体则减少高糖刺激的TLR4表达。因此，本课题提出PAF受体参与高糖刺激TLR4活化的假说，分析PAF受体在高糖刺激TLR4活化中的作用；探讨Akt、p38MAPK、Erk等信号分子对TLR4表达的调控作用；探讨银杏内酯B抑制PAF受体对上述信号分子的影响。本课题还将利用db/db基因缺陷小鼠，建立2型糖尿病动脉粥样硬化小鼠模型。通过分析各组小鼠的斑块面积、TLR4、PECAM-1、VCAM-1等炎症蛋白表达，评价银杏内酯B干预对糖尿病小鼠动脉粥样硬化的影响。本课题对于糖尿病动脉粥样硬化的防治研究具有重要意义。

中文关键词： 人血管内皮细胞；动脉粥样硬化；2型糖尿病；氧化型低密度脂蛋白；糖尿病慢性并发症

英文摘要： Recent, some studies showed that TLR4 expression increase,platelets function change and endothelial cell function injury in diabetes. However, It is needed to clear that the effects of TLR4 expression on platelet function change and endothelial cell injury in diabetes with atherosclerosis.We have found that the high dose of glucose increased TLR4 expression on platelets and endothelial cells. Simultaneously, our result showed that the high concentration of glucese induced PF4 and CD40L release, and PECAM-1 expression in platelets. Similar results were obtained in high glucose treated endothelial cells. The high dose of glucose also challenged PECAM-1 expression in HUVECs. Furthermore, we found that gikgolide B, an inhibitor of PAF receptor,inhibited TLR4 expression induced by high dose of glucose in platelets and HUVECs, respectively. PAF （platelet activating factor）is an endogenous proinflammatory cytokine, which involved in the multifarious inflammatory responses. Therefore, we speculate that PAF receptor might be involved TLR4 activation in platelets and endothelial cells. In the present study, we attempt to explore that the effect of PAF on TLR4 expression in glucose-treated platelets and endothelial cells. To explore the relation of signaling molecule Akt, p38MAPK, and Erk, we will determine the phosphorylation of Akt, p38MAPK, and Erk in glucose-treated platelets or endothelial cells. Meanwhile, we will observe the effect of ginkgolide B on TLR4 expression and above molecules as well as. In addtion , we will perform animal expreienment to investigated the atherogenesis in the ginkgolide B treated db/db mice (a leptin receptor defective mice) and positive mice.We suggested that inhibiting TLR4 expression in platelets and endothelial cells might be a potential therepeutic stategy for preventing atherosgenesis in diabetes.

英文关键词： vascular endothelial cells;atherosclerosis;2 type diabetes;ox-LDL;chronic complication of diabetes mellitus