MID1调控糖稳态的分子机制

糖尿病是现今世界人类面临的重大健康威胁，探索糖尿病的病因及发病机制对寻找糖尿病治疗的潜在靶点具有重要的科学意义。已有研究证实，FGF21可降低血液中葡萄糖和胰岛素的水平，并能增加胰岛素的敏感性；项目组前期研究发现，FGF21可通过激活TFEB信号通路进而抑制E3泛素化连接酶MID1的表达而影响脂代谢。但是，FGF21是否可以通过MID1影响糖代谢，以及MID1调控糖稳态的分子机制并不清楚，仍需系统的研究。本项目拟通过纯化高活性FGF21蛋白进行体内外实验，明确MID1在FGF21调控糖稳态中的作用；利用已有的Mid1基因敲除小鼠，阐明MID1调控糖稳态的代谢表型；综合采用生理学、分子细胞生物学、代谢组学和蛋白质组学等方法，筛选MID1调控糖稳态的下游信号分子，并深入分析MID1调控糖稳态的分子机理。该项目旨在为制定糖尿病诊疗新方案奠定坚实的理论基础，并对糖尿病药物的研发提供重要的科学依据。

Diabetes is a major threat to human health around the world. It is of great scientific significance to explore the etiology and pathogenesis of diabetes in order to seek for potential target of diabetes treatment. It has been confirmed that FGF21 can reduce the glucose and insulin level in the blood and increase the sensitivity of insulin. Our previous studies found that FGF21 could affect lipid metabolism by activating TFEB signal pathway and inhibiting the expression of E3 ubiquitin ligase MID1. However, a systematic research is still needed to investigate whether FGF21 can regulate glucose metabolism through MID1, since the molecular mechanism of glucose homeostasis affected by MID1 is underexplored. In this project, we intend to clarify the role of MID1 in the regulation of glucose homeostasis by FGF21 through purifying high activity FGF21 protein. Additionally, we will illuminate the metabolic phenotype of MID1 regulating glucose homeostasis by using the existing Mid1 knockout mice. Lastly, we will screen for the downstream signal molecules of MID1 and systematically analyze the molecular mechanisms of MID1 regulating glucose homeostasis with the combined methods of physiology, molecular cell biology, metabonomics and proteomics. The project aims to lay solid theoretical foundation for the development of new diagnosis and treatment strategy of diabetes, and provide an important scientific basis for the research and development of diabetes drugs.