过氧化物酶体増殖物激活受体γ（PPARG）基因Y95C错义突变的致病作用与机理研究

过氧化物酶体增殖物激活受体γ(PPARG)是一种配体依赖性的转录因子，在脂肪细胞分化、脂肪生成、葡萄糖稳态和炎症中起关键作用。PPARG罕见变异可能引起家族性部分脂肪营养不良、胰岛素抵抗和糖尿病（PPARG-DM）。. 目前尚无中国人群PPARG-DM的报道，我们前期研究发现PPARG-DM与高加索人群发病率类似，且发现了PPARG基因错义变异Y95C可能是中国人群中特有的PPARG-DM热点变异，该变异在体外实验中显示可能是通过影响PPARG SUMO化进而影响PPARG功能，但尚未在体内实验中证实。. 本项目构建PPARG-Y95C突变敲入小鼠模型研究该变异的致病作用及可能的致病机制。为进一步明确糖尿病相关的病理生理机制做出新贡献，还将从科学上为TZDs的精准治疗提供科学依据，和开发更有效的针对PPARG的药物提供新的依据，促使基础研究成果向临床转化。

Peroxisome proliferator-activated receptor γ (PPARG) is a ligand-dependent transcription factor that plays a key role in adipocyte differentiation, adipogenesis, glucose homeostasis, and inflammation. Rare variants in PPARG may cause familial partial lipodystrophy, insulin resistance, and diabetes (PPARG-DM). .At present, there is no report on PPARG-DM in the Chinese population. Our study found that the prevalence of PPARG-DM is similar to that of the Caucasian population, and found that a missense variant-Y95C of PPARG gene might be a is a Chinese specific causative variant for diabetes. This variant might affect the function of PPARG by affecting PPARG SUMOylation in vitro, but it has not been confirmed in vivo. .In this project, a mouse model of PPARG-Y95C mutant knock-in was constructed to study the pathogenic effect of the mutation and its possible pathogenic mechanism. To make a new contribution to further clarify the pathophysiological mechanism of diabetes, it will also provide a scientific basis for the accurate treatment of TZDs, and provide a new basis for the development of more effective drugs for PPARG, to promote the transformation of basic research results into clinical practice.