人体内固醇中含量最为丰富的胆固醇既是膜性细胞器的膜结构组成、又具有极重要的功能调控作用，而胆固醇代谢失衡会导致动脉粥样硬化、神经退行性疾病等病变。我们前期工作发现溶酶体-过氧化物酶体形成膜接触介导胆固醇运输、阐明小肠胆固醇吸收分子途径及内源胆固醇合成负反馈调控通路、揭示胆固醇酯合成酶的基因表达与蛋白降解调控，成果发表在Cell、Science、NCB、Cell Metab等期刊上。在此基础上，本申请项目将利用体细胞遗传筛选等技术体系，鉴定新的调控胆固醇合成及介导胆固醇从内质网向质膜运输的基因、蛋白，已有结果表明内质网-线粒体-质膜之间的互作对胆固醇合成、运输至关重要，本项目将深入研究上述细胞器互作对固醇代谢稳态的功能调控，鉴定介导细胞器膜接触及调控胆固醇合成与运输的关键蛋白因子，深入揭示其在固醇代谢稳态中的作用。

Cholesterol is the most abundant sterol in humans. It regulates membrane functions. But disturbed cholesterol metabolism causes atherosclerosis and neurodegeneration diseases. Cholesterol homeostasis requires the elegant regulations on cholesterol biosynthesis, intestinal cholesterol absorption and intracellular cholesterol transport. We have identified that lysosome-peroxisome membrane contacts facilitate cholesterol transport from lysosomes to peroxisomes. We have also uncovered the mechanism of intestinal cholesterol absorption, delineated the feedback regulatory pathway of cholesterol biosynthesis, and discovered the splicing and degradation regulation of ACATs. The results have been published in Cell, Science, NCB, Cell Metab and et al. Based on the previous studies, this proposal will use somatic cell screening to identify new genes involved in cholesterol biosynthesis and transportation to plasma membrane from ER. We have finished the screening and our preliminary data suggest that ER-Mitochondria-plasma membrane contacts play an essential role in cholesterol biosynthesis and plasma membrane targeting. We will further investigate the mechanisms of these membrane contacts and identify important proteins in sterol homeostasis.