GRP75通过非线粒体相关内质网膜依赖途径调控机体胰岛素敏感性的机制研究

线粒体相关内质网膜（MAM）及其组分在2型糖尿病（T2D）发生发展中的作用一直存在争论。在前期工作中，我们发现敲降MAM组分蛋白GRP75能够在不改变MAM功能的前提下，降低细胞胰岛素敏感性。此外，我们首次发现GRP75极有可能直接参与氧化磷酸化复合体（OXPHOS）的组装，并可能以非MAM依赖的途径激活TNF信号通路。为了验证这一调控途径，我们将以细胞和GRP75条件敲除小鼠模型为研究对象，利用复合体组学等蛋白相互作用技术明确GRP75与OXPHOS装配的关系；通过细胞生物学等技术揭示GRP75通过调控OXPHOS装配影响线粒体功能的机制并进一步调节TNF信号通路的线粒体-核交流本质，最终明确GRP75调控胰岛素抵抗和T2D发生的机制。最后，我们希望以GRP75治疗靶点，通过干预GRP75/TNF信号通路在T2D治疗中的作用，探讨基于GRP75表达水平的T2D精准检验和治疗价值。

The role of mitochondrial-associated endoplasmic reticulum membrane (MAM) and its components in the development of type 2 diabetes (T2D) has been controversial. In previous work, we found that knocking down MAM component protein GRP75 can reduce cellular insulin sensitivity without changing the function of MAM. Combined with genome-wide expression profiling, we found for the first time that GRP75 is likely to directly participate in the formation of oxidative phosphorylation complex (OXPHOS) and activate the TNF signaling pathway in a MAM-independent manner. In order to verify this regulatory pathway, we will take cells and GRP75 conditional knockout mouse models as research objects, and use protein-interaction techniques such as complex omics to clarify the relationship between GRP75 and OXPHOS assembly; through cell biology and other technologies, reveal the mechanism that regulates OXPHOS assembly affects mitochondrial function and further regulates the nature of mitochondrial-nuclear communication of TNF signaling pathway, and finally clarifies the mechanism of GRP75 regulating insulin resistance and T2D. Finally, with GRP75 treatment targets, through the intervention of the role of GRP75/TNF signaling pathway in T2D therapy, the precise T2D test and therapeutic value based on the expression level of GRP75 was clarified.