FSTL1促糖尿病动脉粥样硬化斑块发生及机制研究

项目名称： FSTL1促糖尿病动脉粥样硬化斑块发生及机制研究

项目编号： No.81470547

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： 杨克

作者单位： 上海交通大学

项目金额： 73万元

中文摘要： 糖尿病动脉粥样硬化病变程度高，需明确其发病机制。现发现：糖尿病动脉粥样硬化中FSTL1分泌升高，而斑块中巨噬细胞主要表达该分子，其促进了巨噬细胞脂质累积、炎症及增殖。FSTL1受体为RAGE、TLR4、CD14及TLR2，RAGE调控其表达，而FSTL1促进TLR4-CD14-CD209形成复合物，并激动了TLR2/4下游信号通路。这提示了FSTL1通过多重调控作用促进巨噬细胞病理改变是糖尿病动脉粥样硬化进展的重要机制。因此，本研究将探讨：1）RAGE与FSTL1相互关系2）FSTL1与受体结合位点3）FSTL1调控复合体形成及其对巨噬细胞脂质累积、炎症及增殖的影响4）FSTL1对TLR2/4下游信号通路调控作用5）在体研究FSTL1对糖尿病动脉粥样硬化进展的影响。以期阐明FSTL1对糖尿病动脉粥样硬化斑块进展的调控机制，为在体干预治疗糖尿病动脉粥样硬化斑块提供重要的科学依据和实验基础。

中文关键词： 动脉粥样硬化；糖尿病血管病变；巨噬细胞；FSTL1；炎症反应

英文摘要： The pathological of atherosclerosis with diabetic is more serious，but the mechanisms is not clear. In the present study, we found that the level of FSTL1 is increased in atherosclerosis with diabetic，and it expressed in the macrophages of diabetic human and animal plaque. FSTL1 promoted lipid accumulation, inflammatory and proliferation, and RAGE, TLR4, CD14 and TLR2 as its receptors have been detected. AGEs is positive related to FSTL1 and regulated it expression. Moreover, FSTL1 increase TLR4-CD14-CD209 forming complex and TLR2/4 pathway activation. All of these result hints that FSTL1 regulated the function of macrophages in atherosclerosis with diabetic via multiple pathways. This study is aimed at achieving mechanistic understanding of: 1. The relationship between with RAGE and FATL1. 2. The site of FSTL1 binding with RAGE, TLR4, CD14 and TLR2. 3. FSTL1 regulates the complex of TLR4-CD14-CD209 to affect lipid accumulation, inflammatory and proliferation in macrophages. 4. FSTL1 regulates the pathway of TLR2/4. 5. The affection of FSTL1 promotes the atherosclerosis with diabetic in vivo. This study will demonstrate the exact roles of FSTL1 and macrphages in the pathogenesis of diabetic with atherosclerosis, and aid the design of strategies for clinical treatment of diabetic with atherosclerosis.

英文关键词： Atherosclerosis;Diabetic angiopathy;Macrophage;FSTL1;Inflammatory