胆固醇酯转运蛋白在息肉状脉络膜血管病变发病中的作用机制研究

项目名称： 胆固醇酯转运蛋白在息肉状脉络膜血管病变发病中的作用机制研究

项目编号： No.81200705

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： 张雄泽

作者单位： 中山大学

项目金额： 23万元

中文摘要： 息肉状脉络膜血管病变（PCV）是我国老年人群高发的不可逆致盲性眼病。申请人前期研究中首次鉴定出胆固醇酯转运蛋白（CETP）基因与PCV发病强相关，并发现该基因变异下调PCV患者血清高密度脂蛋白（HDL）；预实验表明HDL所携带的α1抗胰蛋白酶也同时下调。鉴于小鼠过度表达弹性蛋白酶HTRA1可诱发PCV，而α1抗胰蛋白酶可结合HTRA1抑制其活性，提示CETP通过HDL相关的细胞外基质代谢参与PCV发病。本项目在功能遗传学层面调查CETP基因致人群易感PCV的作用机制，分析CETP基因变异对PCV患者CETP活性、HDL颗粒及所附α1抗胰蛋白酶水平、α1抗胰蛋白酶-HTRA1复合物形成以及下游细胞外基质代谢通路的影响，并在小鼠体内观察沉默α1抗胰蛋白酶后脉络膜组织病理学以及通路上下游分子的表达变化。本项目联汇CETP脂代谢通路和HTRA1细胞外基质代谢通路，有望为PCV防治提供新的干预路径。

中文关键词： 息肉状脉络膜血管病变；胆固醇酯转运蛋白；弹性蛋白酶；细胞外基质；HtrA1丝氨酸蛋白酶

英文摘要： Polypoidal choroidal vasculopathy (PCV) is the leading cause of irreversible vision impairment among Chinese elderly. Our previous study first indentified that cholesteryl ester transfer protein (CETP) gene was significantly associated with the risk of PCV. We also observed that the risk allele of CETP decreased the serum level of high-density lipoprotein (HDL) in patients with PCV. Our preliminary experiment demonstrated that α1-antitrypsin, an elastase inhibitor carried by HDL, was also influenced by CETP risk variant. Overexpression of HTRA1, which has elastase activity, could induce PCV. Furthermore, α1-antitrypsin can bind to and form a stable complex with HTRA1. These findings indicate the function of CETP in regulating elastase inhibitor carried by HDL, which involve in the pathogenesis of PCV. This study was designed to investigate the biological plausibility of the association between CETP risk variant and PCV. The regulation function of CETP variant will be studied in serum CETP mass and activity, HDL level and particle size, α1-antitrypsin level, formation of α1-antitrypsin-HTRA1 complex, and downstream extracellular matrix-related factor regulated by HTRA1. The remodeling of Bruch membrane and choroidal vessels and the expression of each member in this pathway will be observed in a mice model with sh

英文关键词： polypoidal choroidal vasculopathy；cholesteryl ester transfer protein；elastase；extracellular matrix；HtrA serine peptidase 1