髓样分化蛋白-2在糖尿病视网膜病变中的作用机制研究

Chronic inflammation plays an important role in the progress and development of diabetic retinopathy (DR). TLR4/MD2 is an important mediator for LPS-induced inflammatory response. Recently, studies on DR patients and animal showed the overexpression of TLR4 in retina tissues 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 DR is yet unkown. In the previous studies on anti-inflammatory drug design and evluation, our lab found several novel molecules, which directly targeted MD2 protein and possessed excellent anti-inflammatory activity in LPS-stimulated models. Importantly, oral administration of compound E56 was found to significantly attenuate retina injury 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 retina inflammation and DR, and inhibition of MD2 may contribute to the treatment of DR. A series of studies are designed to test and perform our hypothesis. These include, 1) to investigate the TLR4/MD2-dependent mechanism by which E56 inhibits HG-induced inflammation in retinal pigment epithelial cells and macrophages, 2) to probe the MD2-mediated pharmacology and pharmacodynamics of E56 in type 1 diabetic mice, 3) and to demonstrate the important role of MD2 in DR development using MD2-/- mice. There is an urgent demand to develop more reliable drug target and treatment in diabetic comlications containing DR. Completion of this challenge project not only has high scientific impact on understanding the MD2-involved mechanism in diabetic retina inflammation and DR, but also provides new target and strategy for the treatment of DR.

慢性炎症是糖尿病视网膜病变（DR）的主要病理因素之一。TLR4/MD2是介导内毒素LPS急性炎症的重要受体复合物，也有研究表明TLR4在DR视网膜组织中高表达并介导DR中炎症反应。但是MD2是否参与非LPS条件下的DR炎症反应？MD2在DR中的作用尚无报道。本实验室前期工作寻找到可以直接结合并抑制MD2、具有优秀抗LPS炎症活性的小分子E56；口服E56可以显著缓解1型糖尿病小鼠视网膜损伤。基于此，我们假设：MD2在DR炎症病理进程中有着重要的介导作用，抑制MD2可以缓解DR的发生发展。本项目中，我们拟利用视网膜细胞、糖尿病模型和MD2-/-小鼠，探讨MD2在DR发生发展及高糖炎症中的作用，在E56抑制高糖炎症反应中的介导作用及其对TLR4的依赖；继续阐明E56防治DN的靶点和药理药效。项目实施将明确MD2介导的炎症反应在DR中的作用，证实MD2可以作为DR防治的新靶点，提供新的治疗策略。

慢性炎症是糖尿病视网膜病变（DR）的主要病理因素之一。TLR4/MD2是介导内毒素LPS急性炎症的重要受体复合物，也有研究表明TLR4在DR视网膜组织中高表达并介导DR中炎症反应。但是MD2是否参与非LPS条件下的DR炎症反应尚未被阐明，MD2在DR中的作用也无报道。本实验室前期工作发现可以直接结合并抑制MD2、具有优秀抗LPS炎症活性的小分子E56；口服E56可以显著缓解1型糖尿病小鼠视网膜损伤。基于此，我们假设MD2在DR炎症病理进程中有着重要的介导作用，抑制MD2可以缓解DR的发生发展。本项目中，我们利用视网膜细胞、糖尿病模型和MD2-/-小鼠，探讨了MD2在DR发生发展及高糖炎症中的作用。我们的数据表明MD2通过介导高糖诱导的炎症反应，促进DR的发展，MD2可作为治疗DR的有效靶点。我们的研究可为临床DR的治疗提供新的治疗策略。