高磷血症致胆固醇敏感器SCAP功能失调促进动脉粥样硬化的分子机制研究

项目名称： 高磷血症致胆固醇敏感器SCAP功能失调促进动脉粥样硬化的分子机制研究

项目编号： No.81500341

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 周超

作者单位： 重庆医科大学

项目金额： 18万元

中文摘要： 动脉粥样硬化性疾病是慢性肾脏病患者最常见的并发症和首要死亡原因。大量研究发现血磷增高能够显著增加慢性肾脏病患者动脉粥样硬化性疾病的发生率，但机制并不清楚。胆固醇敏感器SCAP介导的对LDL受体活性的负反馈调节是维持细胞内胆固醇稳态的重要生理机制。我们前期研究发现：高磷状态能够促进原代人VSMCs内脂质聚集，并呈剂量依赖性地增加胆固醇敏感器SCAP的表达，促进其向高尔基体异常转位。因此，我们推测，高磷血症可能通过诱导胆固醇敏感器SCAP功能失调促进细胞内脂质积聚及动脉粥样硬化的发生。.本项目拟通过细胞试验、动物实验、人动脉血管环培养及临床病例对照研究，探索高磷血症促进动脉粥样硬化性疾病的分子机制，并从分子、细胞和整体水平系统评价降血磷治疗对防治高磷血症所致动脉粥样硬化性疾病的效果。研究结果可能为高磷血症所致动脉粥样硬化性疾病的防治提供潜在的新靶点，并为降血磷药物的临床应用提供新的理论依据。

中文关键词： 动脉粥样硬化；高磷血症；胆固醇敏感器；慢性肾脏病；低密度脂蛋白

英文摘要： Atherosclerotic disease is the most common complication and the main cause of death in the population suffering from chronic kidney disease(CKD). Mounting evidence showed a strong link between higher serum phosphate level and greater incidence of atherosclerotic disease. However, the mechanism remains unknown. The negative feedback regulation of LDL receptor (LDLr), which is mediated by cholesterol sensor- Sterol Regulatory Element Binding Protein (SREBP) Cleavage Activiting Protein (SCAP), is the most crucial mechanism for the maintaince of the intracellular cholesterol homeostasis. Our previous study indicated that hyperphosphatemia promoted lipid accumulation in primary human vascular smooth muscle cells (hVSMCs), and increased the expression of SCAP in a dose dependent manner, which might lead to the aberrant translocation of SCAP from ER to Golgi. We supposed that hyperphosphatemia may promote intracellular lipid accumulation and atheroma progression by inducing the dysfunction of SCAP. . This study will target the mechanisms by which hyperphosphatemia promotes atherosclerosis. The methods of cell culture, animal experiments, human vascular ring culture and clinical case-control study will be used to examine our hypothesis— hyperphosphatemia disrupts SCAP mediated cholesterol homestasis feedback regulation, by which it upregulates the expression of LDLr and HMGCoAR, facilitates excessive exotic LDL uptake and intracellular cholesterol denove synthesis, results in excessive lipid accumulation in the cells and the progression of atheroma. The effectiveness of serum phosphorus control to the prevention and treatment of atherosclerotic disease will be evaluated, which is expected to give indications for the prescription of phosphate binding agents during clinical practice. 

英文关键词： Atherosclerosis;Hyperphosphatemia;Cholesterol Sensor;Chronic Kidney Disease;Low Density Lipoprotein