基于小分子探针的糖脂代谢调控机理研究

Disorder of glucolipid metabolism is associated with a lot of diseases including cardiovascular disease, diabetes, obesity and fatty liver disease. Glucose and lipid metabolism is regulated at multiple levels, and it consists of cholesterol synthesis, ER-stress, mitochondrial dysfunction induced regulation and etc. Many small molecular compounds can target the crucial steps of these signaling pathways to maintain the balance of glucose and lipid metabolism. Our integrated project is based on the previous work, in which some molecular compounds with high regulation activity have been identified. We plan to synthesize probes with these small molecular compounds, and use them to elucidate the key proteins and target sites in cholesterol synthesis pathway, IRE1α-XBP1 and FXR/ER-stress signaling pathway, mitochondrial UCP2 induced regulation and acidification induced molecular pathway. Moreover, the new regulatory mechanism of glucose and lipid metabolism balance will be explored. Then, these small molecular compounds will be optimized and subjected to structure analysis in order to develop a lead compound. At last, we will utilize mouse models of atherosclerosis, diabetes, obesity and other diseases to evaluate their physiology function, which lays the foundation for the further development of drugs to treat disorder of glucolipid metabolism.

糖脂代谢紊乱与心血管疾病、糖尿病、肥胖、脂肪肝等疾病的发生密切相关。糖脂代谢调控是多方面、多层次的，包括胆固醇合成代谢调控、内质网应激（ER-Stress） 调控、线粒体功能异常调控等。许多小分子化合物能够作用于以上不同调控通路中的关键节点，调控糖脂代谢。本集成项目以前期已经筛选出的具有调控活性的小分子化合物为基础，设计合成探针，阐明胆固醇合成途径、内质网应激中的IRE1α-XBP1和FXR信号通路、线粒体功能异常蛋白UCP2调控通路、酸化引发的信号转导途径中的重要蛋白因子和关键靶点，探索新的糖脂代谢平衡调控机制。并对高活性的小分子化合物进行结构优化，解析其结构，旨在开发出先导化合物。在动物水平上，利用动脉粥样硬化、糖尿病、肥胖等疾病小鼠模型上评价其逆转糖脂代谢紊乱的功能，为进一步开发治疗糖脂代谢紊乱的药物奠定基础。

心血管疾病、糖尿病、肥胖、脂肪肝等疾病已成为威胁我国国民身体健康和影响生活质量的主要疾病，也给社会带来沉重的经济负担。本集成项目围绕糖脂代谢调控过程中重要的调控通路开展集成深入研究，发现了靶向IRE1α-XBP1 通路小分子化合物在糖脂代谢调控中的作用机制；获得了调控FXR/ER Stress（内质网应激）机制的新型抗2型糖尿病药物先导结构；并利用小分子探针探索线粒体功能相关蛋白调控糖脂代谢的信号通路；进一步，基于重要的糖脂代谢调控蛋白和通路，发现新的活性小分子，并对代谢紊乱疾病进行干预。揭示了细胞内胆固醇转运的新机制，丰富了胆固醇合成代谢的调控机理，阐明了小肠胆固醇吸收的分子途径, 取得了系统性原创成果，圆满完成预期目标，在国际学术界产生重要影响并有良好应用前景。项目在研期间共发表32篇SCI论文，其中IF>20的论文3篇（Cell、Nature Medicine、Chemical Society reviews），IF>10的论文有4篇（2篇Nature communications、1篇Cell Research、1篇Journal of Hepatology）；IF>5的论文有11篇；培养博士后出站7人，博士研究生毕业16人，硕士研究生毕业2人，并以联合培养的方式为国内兄弟单位培养研究生毕业3人；申请专利6项。