TGR5在葡萄膜炎发病机制中的作用研究

葡萄膜炎是我国常见的且很重要的致盲性眼病，其中Behcet病和VKH综合征是最常见、致盲率最高的两种葡萄膜炎类型，自身免疫反应是该病的发病基础。最近我们课题组预实验发现Behcet病和VKH综合征患者中代谢产物胆汁酸的受体TGR5表达水平显著下降。本项目以上述两种疾病为研究对象，探讨TGR5在巨噬细胞和CD4+T细胞中的表达水平以及TGR5受体对巨噬细胞的活化、极化和CD4+T细胞的增殖分化和功能的影响；探讨TGR5信号通路中cMAP、AKT、PIP2、mTOR、NF-κb和炎性小体NLRP3的表达水平以确定TGR5对巨噬细胞的影响机制；通过敲除TGR5受体基因的动物模型葡萄膜炎的严重程度和TGR5受体激动剂对动物葡萄膜炎的发生发展的影响以明确其作用。本研究旨在以TGR5为出发点，探索该受体在这两种最重要的葡萄膜炎疾病的发病机制中的作用，以期寻找葡萄膜炎预防和治疗的新思路。

Uveitis is the most common eye disease leading to blindness.Behcet’s disease and VKH syndrome are two most important and have the higest blindbess rate in China, which are association with autoimmune reaction. Recently, we found that the expression of bile acids receptor TGR5 in patients with Behcet's disease and VKH syndrome was significantly decreased. So this project was to investigate the role of TGR5 in the pathogenesis of the above two uveitis. First, we will study the expression of TGR5 in the macrophages and CD4+T cells from BD patients and VKH patients to illustrate whether TGR5 was associated with these two uveitis. Secondly, we will explore the effect of TGR5 on the activation, polarization of macrophage and the subsequent proliferation ,differentiation of CD4+T cells. we will investigate the expression of cMAP, AKT, PIP2, mTOR, NF-κB and NLRP3 inflammasome to clarify the mechanism of TGR5 signaling pathway on macrophage.Finally, we are going to study the effect of TGR5 on the severity of experimental antoimmune uveitis(EAU) to demonstrate the negative regulatory role of TGR5 in uveitis. These studies are expected to clarify the pathogenesis of the two uveitis and provide a novel strategy in the prevention and treatment for these diseases.