髓样分化蛋白-2（MD2）在糖尿病肾病（DN）中的作用及MD2抑制剂防治DN的机制研究

项目名称： 髓样分化蛋白-2（MD2）在糖尿病肾病（DN）中的作用及MD2抑制剂防治DN的机制研究

项目编号： No.81200572

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学二处

项目作者： 王晶莹

作者单位： 温州医科大学

项目金额： 23万元

中文摘要： 慢性炎症是糖尿病肾病（DN）的主要病理因素之一。TLR4/MD2复合物是内毒素LPS急性炎症的直接介导物，也有研究表明TLR4在DN肾中高表达，并介导高血糖诱导的肾组织炎症反应。但是MD2是否参与其中？关于MD2在DN炎症中的作用尚无报道。本实验室前期工作寻找到三个可以直接结合和抑制MD2，并具有优秀抗内毒素炎症活性的探针小分子；其中小分子D33可以显著缓解1型糖尿病小鼠肾损伤。基于此，我们假设：MD2在DN的炎症病理进程中有着重要的介导作用，抑制MD2可以缓解DN的发生发展。本项目中，我们拟利用细胞实验探讨MD2在D33抑制高糖炎症反应中的介导作用其对TLR4的依赖；利用动物实验探讨三个探针小分子通过抑制MD2-炎症通路缓解DN的药理药效；利用MD2-/-小鼠，探讨MD2靶点在DN发生发展中的重要性。项目实施将明确MD2介导的炎症反应在DN发生发展中的重要作用，为DN防治提供新的靶点。

中文关键词： 糖尿病肾病；MD2；TLR4；炎症；纤维化

英文摘要： Chronic inflammation plays an important role in the progress and development of diabetic nephropathy (DN). TLR4/MD2 complex is a direct mediator in endotoxin (LPS)-induced inflammation. Recently, studies on DN patients and animal showed the overexpression of TLR4 in renal issues and the in vitro evidences demonstrated that TLR4 was involved in high glucose (HG)-induced inflammation. However, whether MD2 plays a role in HG-inflammation and DN is yet unkown. In the previous studies on anti-inflammatory drug design and evluation, our lab found three novel molecules (A12, C12, and D33), which directly targeted MD2 protein and possessed excellent anti-inflammatory activity in LPS-stimulated models. Importantly, oral administration of compound D33 was found to significantly attenuate DN in type 1 diabetic rats. In view of these results, we hypothesize here, that MD2 may play an important role in the development of diabetic renal inflammation and DN, and inhibition of MD2 may contribute to the treatment of DN. A series of studies are designed to test and perform our hypothesis. These include, 1) to investigate the TLR4/MD2-dependent mechanism by which D33 inhibits HG-induced inflammation in renal epithelial cells and macrophages, 2) to probe the MD2-mediated pharmacology and pharmacodynamics of three mol

英文关键词： diabetic nephropathy；MD2；TLR4；inflammation；fibrosis