机体胆固醇水平过高会引起高脂血症和动脉粥样硬化症等多种人类重大代谢疾病。因此降低血液中的脂质水平，特别是胆固醇水平，从源头预防心血管疾病以及相关代谢性疾病的发生，就尤为重要。实验室前期研究发现胆固醇合成途径中间产物羊毛脂固醇，是一种可特异性抑制胆固醇合成的内源性调控分子。本项目拟根据已发现的调控胆固醇负反馈调控途径的内源小分子结构，一方面对该类化合物进行结构优化和筛选，研究其降胆固醇的构效关系，并在细胞及整体动物水平上系统研究其对脂质代谢平衡及脂质代谢性疾病的影响；另一方面，拟利用慢病毒诱变系统，以调控胆固醇合成途径的活性小分子为选择压力，通过体细胞遗传学方法寻找新的调控胆固醇合成途径调控蛋白因子。该研究将深入揭示胆固醇合成调控的分子机制，并能够筛选鉴定出调控脂代谢的特异活性小分子化合物，发现新的信号转导途径和关键蛋白，为研发具有自主知识产权的代谢异常疾病治疗新药奠定重要基础。

High cholesterol levels cause many metabolic diseases including hyperlipidemia and atherosclerosis. Thus, it is thus important to prevent the development of cardiovascular disease and metabolic diseases by reducing the levels of lipid especially cholesterol in plasma. We previously found that lanosterol, an intermediate product of cholesterol synthesis, acts as an endogenous inhibitor which specifically suppresses the synthesis of cholesterol. In this proposal, on one hand, we will optimize and synthesize a pool of compounds based on the structure of lanosterol. Their structure-function relationship of cholesterol reduction based on their ability to inhibit the activity of HMG CoA reductase will be studied, and the effects of these compounds on lipid metabolic balance and diseases will be further explored using cell and animal models. On the other hand, we will also use somecompounds as negative or positive selectors to find new regulators in cholesterol synthesis using lentivirus mutagenesis system and somatic cell genetic methods. This research will reveal the molecular mechanism of cholesterol synthesis, screen new small compounds with specific activities on lipid metabolism, and identify new signaling pathways and critical proteins on cholesterol synthesis. All these findings will help finding new drug candidates for metabolic diseases.