人GPRC6A的多态性、组成型内化及信号转导在能量代谢调控中的作用与机制

肥胖，糖尿病和非酒精性脂肪肝等能量代谢性疾病目前在世界范围内快速增长，严重影响人类生活和健康。项目组近期研究首次发现并命名的新多肽激素Metabolitin （MTL）通过其受体GPRC6A在小鼠中具备调控糖脂代谢的能力：抑制小肠脂质吸收、缓解脂肪肝症状。然而人GPRC6A在胞内环3的序列上同其他物种不同，该多态性使其可能发生了组成型内化，从而大量定位于细胞内而不是细胞膜上；同时人GPRC6A对糖脂代谢的调控研究仍较为欠缺。因此，本项目将基于前期工作，利用多肽配体MTL和基因编辑的干预手段，在相关靶细胞和动物模型的研究体系中，通过分子间、分子与细胞相互作用以及组织形态和功能等多层面，阐明hGPRC6A的组成型内化和信号转导机制，以及MTL-hGPRC6A系统对糖脂代谢的调控功能，为进一步理解GPCRs的内化机制提供思路与依据，也为将来的药物研发和转化打下坚实的基础。

The energy metabolic diseases such as obesity, diabetes and non alcoholic fatty liver disease are increasing rapidly in the world and seriously affect human life and health. Recently, Metabolitin (MTL), a novel peptide hormone, was discovered and named for the first time by our lab. Metabolitin can regulate glucose and lipid metabolism through its receptor GPRC6A in mice, including inhibiting lipid absorption in small intestine and alleviating fatty liver symptoms. However, compared with other species, human GPRC6a has polymorphism in the sequence of intracellular loop 3, which may result in constitutive internalization, and thus a large number of GPRC6a are localized in the intracellular region rather than on the cell membrane. Also, the molecular mechanism and function of MTL-GPRC6a system in the human body still need to be further explored. Therefore, this project will continue the previous work, by using peptide ligand-MTL and gene editing interventions, in related target cells and animal models, through the aspects of intermolecular, molecular-cell interactions, and tissue morphology and function, explore constitutive internalization and signal transduction mechanisms of hGPRC6A, and energy metabolism regulation function of MTL-hGPRC6A system. The implementation of this study will provide some scientific evidences and further understanding on GPCRs internalization mechanism, also lay foundation for future drug development.