TFPI-2对巨噬细胞胆固醇流入/流出通路的作用及分子机制

项目名称： TFPI-2对巨噬细胞胆固醇流入/流出通路的作用及分子机制

项目编号： No.81200200

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： 潘俊杰

作者单位： 复旦大学

项目金额： 23万元

中文摘要： 泡沫细胞形成堆积、脂质核心增大是动脉粥样硬化（AS）斑块发生、发展的决定因素，而细胞内胆固醇流入和流出平衡失调是导致泡沫细胞形成的关键；组织因子途径抑制物2（TFPI-2）为丝氨酸蛋白酶抑制物家族成员，本课题组新近发现TFPI-2在体内具有抗AS作用，进一步在体外发现其可抑制巨噬细胞泡沫化。据此，本课题首先应用腺病毒载体和siRNA干扰技术分别上调/下调TFPI-2表达，确定其对巨噬细胞泡沫化的作用；并进一步分析其对巨噬细胞胆固醇流入/流出通路中关键基因CD36、PPARγ、LXRα、ABCA1、ABCG1及apoA-I的调节作用；然后干预胆固醇流入/流出通路，观察其对TFPI-2表达的效应以及对巨噬细胞泡沫化作用，以进一步阐明TFPI-2调节巨噬细胞内胆固醇流入/流出平衡、抑制泡沫细胞形成的分子机制。研究结果将确立TFPI-2的抗AS作用，揭示其调节细胞内胆固醇流入和流出平衡的分子机制。

中文关键词： 组织因子途径抑制物 2；动脉粥样硬化；泡沫细胞形成；胆固醇流入/流出；分子机制

英文摘要： The formation and accumulation of foam cells resulted in the augmentation of atherosclerotic lipid core, which played the crucial roles on the occurrence and development of atherosclerotic plaques; Furthermore, the imbalance of cellular cholesterol influx and cellular cholesterol efflux in macrophages was the key to foam cells formation. Tissue factor pathway inhibitor 2 (TFPI-2) is a member of the Kunitz-type family of serine proteinase inhibitor. Our recent researches suggested TFPI-2 had the effects anti-atherosclerosis in vivo, and further its inhibited effects on macrophage-derived foam cells formation in vitro. Based on these results, our further study will be carried out as follow: Initially, we will determine TFPI-2's roles on the foam cells formation of macrophages with adenovirus vector or siRNA's interfered technique unregulated/ downregulated the expression of TFPI-2 respectively in macrophage-derived foam cells model; Meanwhile we will observe what roles TFPI-2's upregulation or downregulation play on some important genes of cellular cholesterol influx/efflux pathway, including the scavenger receptor CD36, peroxisome proliferator-activated receptor gamma (PPARγ), the nuclear receptors liver X receptor alpha (LXRα), ATP-binding cassette transporters A1 and G1 (ABCA1, ABCG1) and Apolipoprotein A-I (ap

英文关键词： TFPI-2；atherosclerosis；foam cells formation；cholesterol influx /efflux；molecular mechanism