项目名称: 动脉粥样硬化进展中TLR4结合并激活Src调控巨噬细胞脂质累积和炎症反应的机制研究
项目编号: No.81200204
项目类型: 青年科学基金项目
立项/批准年度: 2013
项目学科: 医学一处
项目作者: 杨克
作者单位: 上海交通大学
项目金额: 23万元
中文摘要: 动脉粥样硬化斑块发生发展的病理过程中,oxLDL诱导巨噬细胞脂质累积和炎症增加是导致斑块进展的重要病理因素。因此,本研究就将针对这一病理变化的分子机制展开研究,前期研究发现:人冠脉粥样硬化斑块组织中TLR4大量结合并激活Src。而oxLDL诱导巨噬细胞后,Src直接调控脂质累积和炎症反应,并通过TLR4结合和激活Src。这提示oxLDL诱导TLR4结合并激活Src是促进斑块形成的重要机制。因此,本研究将探讨:1.TLR4结合并激活Src特异性结合蛋白结构域;2.特异性阻断TLR4结合Src位点对于细胞脂质代谢和炎症反应的影响;3.动物模型中,特异性阻断TLR4和Src结合对于斑块进展的影响。以期阐明动脉粥样硬化斑块进展中的分子机制,并为将来在体干预治疗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: TLR4;Src;动脉粥样硬化;炎症;脂质
英文摘要: Lipid accumulation and inflammation in macrophage is the major factor that contributes to the progression of atherosclerosis. In the present study, we sought to investigate the molecular mechanism underlying this pathological change. We found that Src phosphorylation and its association with Toll-like receptor (TLR) 4 are increased in human artery atheromatous plaque as compared to normal vessels. In vitro studies showed that OxLDL treatment promoted TLR4 interaction with Src and the activation of Src-dependent signaling pathway, which further enhanced inflammation and lipid accumulation in THP-1 derived macrophage. Thus, this study is aim at demonstrating: 1. the specific binding domain that mediates TLR4-Src association; 2. the effects of blocking the formation of TLR4-Src binding on lipid metabolism and inflammation in macrophage; 3. Inhibition of TLR4-Src formation to attenuate the progression of atherosclerosis in vivo. This study will demonstrate the important roles of Src and TLR4 in the pathogenesis of atherosclerosis, and aid the design of strategies for clinical treatment of atherosclerosis.
英文关键词: TLR4;Src;atherosclerosis;inflammatory;lipid