核受体PPARγ的配体筛选及调控结构机理研究

项目名称： 核受体PPARγ的配体筛选及调控结构机理研究

项目编号： No.31270776

项目类型： 面上项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 李勇

作者单位： 厦门大学

项目金额： 80万元

中文摘要： 过氧化物酶体增殖体激活受体γ (PPARγ）是一种核受体转录因子，在调节血糖平衡和脂肪细胞分化方面具有关键作用。目前临床上用于治疗Ⅱ型糖尿病的噻唑烷二酮(TZD)就是一类PPARγ的激活配体。然而，一些副作用如体重增加、心力衰竭、水肿等严重局限了该类药物的临床使用。因此，研究一种新型、安全、高效的糖尿病治疗药物显得十分迫切。本项目将全面有机结合高通量药物筛选技术、结构生物学、生物化学与分子生物学、药物化学、细胞生物学与糖尿病小鼠模型的研究手段和方法，筛选PPARγ新配体，分析PPARγ与新配体结合的结构机制，研究新配体药物如何通过变构调节来影响PPARγ磷酸化和转录活性，对糖尿病小鼠模型的生理作用及分子机理，旨在获得结构上区别于TZDs的新型高效低毒糖尿病药物的结构设计模板，为获得具有自主知识产权的糖尿病治疗药物提供强有力的理论基础和应用依据。

中文关键词： 核受体；PPAR；结构与功能；配体；

英文摘要： Peroxisome proliferator activated receptor gamma (PPARγ) regulates metabolic homeostasis and is an important molecular target for antidiabetic drugs. While improving insulin sensitivity and lowering plasma glucose levels, the clinical use of TZDs has been tempered by side effects such as edema, weight gain, and increased incidence of heart attack. As such, a new drug design strategy for PPARγ ligands is needed to yield more efficacious PPARγ-targeted drugs with less adverse effect. We plan to screen for novel PPARγ ligands distinct from TZDs from chemical libraries and further determine the crystal structures of the PPARγ complexed with these ligands to study the ligand binding specificity. Moreover, we plan to study the structural basis on how the phosphorylation of PPARγ by Cdk5 is blocked by PPARγ ligands, which is directly linked with the anti-diabetic effects of the ligands. The physilogical effects of the novel ligands will be tested on diabetic mice model. Our research together will reveal important mechanistic understandings for the ligand-regulated phosphorylation of PPARγ and provide templates for designing highly selective and efficient non-thiazolidinedione PPARγ ligands in the treatment of insulin resistance.

英文关键词： Nuclear Receptor；PPAR；Structure and Function；Ligands；