β细胞功能障碍是慢性代谢应激导致机体糖代谢异常的重要环节，β细胞去分化是导致β细胞功能障碍的关键机制。泛素化酶FBXW7通路参与肿瘤代谢的调控机制，但迄今对其与β细胞功能的关系尚未明确。我们发现FBXW7在胰岛β细胞表达丰富，在高脂饮食喂养肥胖小鼠、db/db小鼠β细胞表达降低；敲低FBXW7可能促进MIN6β细胞去分化，过表达FBXW7可能阻断高葡萄糖毒性导致的MIN6β细胞去分化状态；FBXW7可通过泛素化降解下调β细胞去分化关键因子ALDH1A3蛋白表达水平；FBXW7胰岛β细胞选择性敲除小鼠血糖水平较野生型小鼠升高。基于上述工作，本课题将分别从分子、细胞、组织及动物水平，进一步明确FBXW7对β细胞去分化功能的影响作用，确认ALDH1A3通路在其中的作用环节和具体机制。研究结果将阐明FBXW7-ALDH1A3信号通路调控胰岛β细胞去分化功能的重要机制，为防治2型糖尿病提供新靶点。

Type 2 diabetes mellitus (T2DM) and its complications are becoming a major global health burden. β-cell dysfunction is a key feature of T2DM, and mediates the abnormal of glucose homeostasis caused by chronic metabolic stress. Although chronic metabolic stress (eg. obesity or nutrient overload) has been shown to impair β-cell function, the underlying mechanism remains unclear. A thorough understanding of the pathogenesis of β-cell failure will help to develop more therapeutic strategies against diabetes by relieving metabolic stress in β-cell. β-cell dedifferentiation is the key mechanism leading to β-cell dysfunction. Preventing dedifferentiation of β-cell is an important potential therapeutic target for diabetes mellitus. The tumor suppressor FBXW7 is responsible to genotoxic stress, thereby controlling cell proliferation and differentiation in malignant tumors. Apart from these established roles, FBXW7 has recently been shown to contribute to the development of metabolic disorders including fatty liver disease. Recently, we showed that FBXW7 was abundant in pancreatic β cells and decreased in high-fat diet induced obese mice and db/db mice. FBXW7 knock-down might promote the dedifferentiation of MIN6 β cells; overexpression of FBXW7 might block the high-glucose toxicity induced dedifferentiation of MIN6 β cells; FBXW7 could down-regulate the expression level of ALDH1A3, the key factor of β-cell dedifferentiation through ubiquitination degradation. The blood glucose level of FBXW7 islet β-cell selective knockout mice was higher than that of wild-type mice. Based on these results, we aim to clarify the effect of FBXW7 on the dedifferentiation of β cells and the specific mechanism of ALDHA3 pathway at the molecular, cellular, tissue and animal levels, by using the previously established transgenic animal models. The results will elucidate the important mechanism of FBXW7-ALDH1A3 signaling pathway on the dedifferentiation of pancreatic β-cell, and provide a new target for the prevention and treatment of type 2 diabetes. The results will provide new insight into the fundamental mechanisms of β-cell function and regulation of β-cell dedifferentiation, and to shed new light on the pathogenesis of glucose dysregulation in diabetes. The unique mouse model established in this study will serve as a useful tool to identify and validate novel drug targets for the development of therapeutics to combat diabetes, one of the major chronic disease in China.