Bruton酪氨酸激酶致糖尿病肾脏巨噬细胞激活的作用及分子机制

项目名称： Bruton酪氨酸激酶致糖尿病肾脏巨噬细胞激活的作用及分子机制

项目编号： No.81470965

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： 吴永贵

作者单位： 安徽医科大学

项目金额： 73万元

中文摘要： Bruton 酪氨酸激酶(Btk)是非受体类酪氨酸激酶Tec家族成员之一，研究发现它是TLR信号通路的一个关键分子。我们前期发现巨噬细胞TLR下游信号通路的活化可增强肾脏炎症反应与糖尿病肾病(DN)发生、发展，预实验发现糖尿病小鼠肾组织及高糖培养的巨噬细胞p-Btk表达增加，Btk抑制剂可抑制高糖环境下巨噬细胞激活。因此，我们假设Btk可能通过激活促炎症信号通路活化肾脏巨噬细胞，促发炎症反应，参与DN的发生、发展。本研究拟采用小鼠糖尿病模型、体外高糖培养的巨噬细胞为主要研究对象，应用Btk 基因敲除小鼠、RNA干扰等手段，观察肾脏巨噬细胞Btk与DN的相关性，并明确其与TLR下游的MAPK和NF-κB信号通路及JAK/STAT1和PI3K/Akt信号通路活化的关系，深入探讨Btk调控巨噬细胞活化的分子机制。本项目的实施有望为DN的防治提供新的思路和线索。

中文关键词： 糖尿病肾病；巨噬细胞；Bruton酪氨酸激酶；炎症

英文摘要： Bruton's tyrosine kinase (Btk), a member of the Tec family of non-receptor tyrosine kinases, has been demonstrated to be an important molecular of Toll-like receptor (TLR) signal pathway. In provious study, we found out that activation of the downstream proinflammatory pathways of TLR in renal macrophages could lead to the enhancement of inflammatory response in the kidney and the development and progress of diabetic nephropathy (DN). Our preliminary experiments showed that p-Btk expression was increased in renal tissue from diabetic mice and macrophages cultured in high glucose, and Btk inhibitors could inhibit the activation of macrophages. Therefore, we hypothesize that Btk can activate proinflammatory pathways in renal macrophages, resulting in inflammatory response in the kidney, and involves the development and progress of DN. In this study, diabetic model of mice and macrophages cultured in high glucose are utilized. The main object of study is the renal macrophages and Btk knock out and RNA interference are also used. We aim to investigate the impact of renal macrophage Btk on the development and progress of DN, and study the relation of Btk to the activation of downstreams of including MAPKs and NF-kapa B as Well as other signal pathway such as JAK/STAT1 and PI3K/Akt. Based on the above experiments, the molecular mechanism of Btk to regulate renal macrophage activation will be deeply studied. The results of this study will provide new ideas and targets in the prevention and management of DN.

英文关键词： diabetic nephropathy;macrophage;Bruton's tyrosine kinase;inflammation