NFκB信号通路调节巨噬细胞胆固醇平衡在尿毒症性动脉粥样硬化发病机制中的作用研究

项目名称： NFκB信号通路调节巨噬细胞胆固醇平衡在尿毒症性动脉粥样硬化发病机制中的作用研究

项目编号： No.81200541

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学二处

项目作者： 申燕

作者单位： 西安交通大学

项目金额： 23万元

中文摘要： 尿毒症患者高发的动脉粥样硬化（AS）相关疾病已成为影响其生存率和致残率最重要的因素，目前其加速AS发展的发生机制不十分清楚。巨噬细胞内胆固醇堆积形成泡沫细胞是AS的重要发病机制，胞内胆固醇含量取决于其入胞、出胞之间的平衡及其代谢相关酶的数量和活性。本研究拟在前期建立尿毒症性AS动物模型（尿毒症apoE-/-小鼠）的基础上，结合离体研究，观察：①尿毒症对AS发生发展和斑块稳定性的影响；②尿毒症模型鼠加速发展的AS与巨噬细胞NFκB活性、胆固醇平衡的关系；③通过构建NFκB过度表达（转基因）/NFκB表达抑制（iRNA沉默NFκB基因）的巨噬细胞，观察上调/下调NFκB信号对胞内胆固醇平衡的调节作用；④在体观察移植基因重组的巨噬细胞对胆固醇平衡及AS发展、斑块稳定性的影响；⑤抗氧化剂NAC对巨噬细胞NFκB活性、胆固醇平衡和AS的影响。为探寻尿毒症性AS发病机制和潜在治疗靶提供分子细胞学依据。

中文关键词： 慢性肾功能不全；动脉粥样硬化；硫酸吲哚酚；巨噬细胞；泡沫细胞

英文摘要： Atherosclerosis (AS)-related disorder has become the most important factor influencing the survival and mutilation in patients with uremia, the mechanisms involved in the accelerated AS in uremia remain unclear yet. It's known the formation of foam cells (lipid-laden macrophages) is a hallmark of AS, cholesterol content of macrophage is determined by the balance of cholesterol influx and efflux, and the quantity and activity of enzymes involved in cholesterol metabolism. In the previous study, we have established an animal model of uremic AS (uremic apoE?/? mouse), based on that and ex vivo experiments, this study is aimed to: ① investigate the influence of uremia on the genesis and development of AS, and the stability of plaque; ② investigate the relationship between the accelerated AS in uremic model mouse and nuclear factor-κappaB (NFκB) activity, and cholesterol balance of macrophage; ③ investigate the influence of up-regulation and down-regulation NFκB on cholesterol balance of macrophage by constructing the macrophages of NFκB overexpression (transgene) and NFκB inhibited-expression (iRNA silence NFκB gene); ④ investigate the influence of transplanting macrophages of gene recombination on cholesterol balance, AS progression, and the stability of plaque in vivo; ⑤ investigate the influence of antioxidant N-

英文关键词： Chronic renal insufficiency；Atherosclerosis；Indoxyl sulfate；Macrophage；Foam cell