遗传性LCAT缺陷症抗动脉粥样硬化发生的分子机制

Atherosclerosis (AS) is a serious harmful disease for human. There is an inverse correlation between the plasma concentration of high-density lipoprotein cholesteral(HDL-C) and incident of AS. The plasma concentration of HDL-C in the patients with LCAT deficiency is extremely low, but they seldom suffered from AS. Based on this special clinical phenomenon, we hypothesized that there may exist some compensatory anti-atherogenic mechanisms in the reverse cholesterol transport (RCT),endoplasmic reticulum stress and autophagic response in macrophage.We plan to use macrophage of LCAT gene knockout mice, to analyze the related genes and proteins which involved in the RCT, ER stress and autophage. And we will resequence the LCAT gene in the patients with very low HDL-C levels. We hope this study can reveal the molecular mechanism of anti-athrogenic factors in this special patients group,and can provide the new insight of personalized anti-atherosclerosis strategy or pharmacogenomics.

动脉粥样硬化（AS）是严重危害人类健康的疾病。高密度脂蛋白胆固醇(HDL-C)水平与AS发生呈负相关。临床中发现LCAT缺陷症患者血浆HDL-C水平极低,但却较少发生AS。本课题以这一特殊临床现象作为切入点，提出了"遗传性LCAT缺陷症所致低HDL-C血症会存在代偿性胆固醇逆转运(RCT)，以及减少巨噬细胞内质网应激和增加细胞自噬的机制，从而起到抗AS发生发展"的假设，拟应用LCAT基因敲除小鼠肝脏及腹腔内巨噬细胞为研究对象，对参与胆固醇逆转运、内质网应激以及细胞自噬的分子标志物进行分析。同时对临床中低HDL-C人群的LCAT基因进行重测序。本研究将初步揭示遗传性LCAT缺陷症这一特殊低HDL血症人群中抗AS的分子机制，并探索该人群中LCAT基因的变异情况，为我国AS的个体化治疗暨药物基因组学提供新的线索。