AMPK作为细胞能量感受器，具有调节细胞能量代谢的作用。AMPK与细胞生长、自噬及多种代谢途径密切相关，其信号途径是研究糖尿病及其他代谢相关疾病的核心。然而AMPK自身的激活调控机制仍不十分清楚。本项目首次发现去泛素化修饰在AMPK激活过程中发挥重要作用，且鉴定了首个AMPK去泛素化酶USP10，并发现USP10-AMPK通路受到精细的调控。因此本项目将有助我们对AMPK信号转导通路调控及其生物学功能的认识，为糖尿病等其他代谢性疾病提供新的药物靶标。我们将在分子、细胞及动物模型水平上研究USP10去泛素化AMPK在AMPK激活过程中的作用及其分子机制：1.USP10调控AMPKα去泛素化及其活性的分子机制；2.USP10去泛素化AMPK的调控机制；3.USP10肝脏异敲除小鼠模型的建立及表型分析；4.AMPK介导的USP10磷酸化位点的确定以及临床肿瘤病理的突变筛查。

AMP-activated protein kinase (AMPK) is a crucial cellular energy sensor. In response to energy depletion, AMPK activation promotes metabolic changes to maintain cell proliferation and survival. As a key player in cell energy metabolism, AMPK has important role in diabetes and related metabolic diseases. However, the AMPK activation mechanism remains elusive. Here, we identified USP10 as the first deubiquitinating enzyme that regulates the AMPK phosphorylation and activities. Further, we reveal the regulation mechanism of USP10-AMPK signal transduction pathway, which will significantly advance our understanding of AMPK function in biology. In the current application, we propose the following Specific Aims: (1) How does USP10 regulate AMPK deubiquitination and function? (2) The detailed regulatory mechanisms of USP10-AMPK pathway; (3) Function study of USP10 liver-specific knockout mice; (4) Investigation of usp10-AMPK pathway in clinical samples.