Rheb1和Grb10基因对胰岛β细胞功能影响及mTOR信号通路调控的机制研究

我们最近在国际上首次报导胰腺组织特异性敲除生长因子受体结合蛋白10（Grb10）导致小鼠胰岛β细胞增殖及胰岛素分泌显著增强，作用机制仍不清楚(Zhang et al.(2012)Diabetes)。我们发现敲除Grb10导致β细胞mTOR信号通路明显增加。结合已有报道mTOR信号通路促进β细胞增殖和胰岛素分泌，我们推测Grb10可能是mTOR信号通路的关键负调控因子，而解除β细胞Grb10对mTOR信号通路的负调控为β细胞增殖及胰岛素分泌增加的重要分子机制。Rheb1是mTORC1直接正调控因子，本项目在国际上首次应用胰岛β细胞特异性Rheb1基因敲除小鼠及β细胞特异性Rheb1/Grb10双基因敲除小鼠对这个科学假说进行探讨。该模型不仅研究mTOR信号通路，更重要是探讨mTOR信号通路介导Grb10在β细胞的功能。其结果将明确β细胞mTOR信号通路调控新机制，为糖尿病治疗和预防提供新思路

We have reported for the first time that pancreas-specific knockout of the Grb10 gene led to increased pancreatic β cell proliferation and insulin secretion (Zhang et al. (2012) Diabetes 61(12): 3189-98）. However, the underlying mechanisms remain unknown. We found that ablation of Grb10 in pancreas led to increased insulin and mTOR signaling（Zhang et al. (2012) Diabetes 61(12): 3189-98）. Taken together with the finding that mTOR signaling stimulated pancreatic β cells proliferation and insulin secretion（Rachdi et al. (2008) Proc Natl Acad Sci USA 105:9250-9255）, we hypothesize that Grb10 is a key negative regulator of mTOR signaling in β cells and diminishing the negative regulation of Grb10 on mTOR signaling could be the mechanism underlying the enhanced proliferation and insulin secretion in β cells. In this project, we will determine if pancrecatic β cell-specific knockout of Rheb1, an upstream activator of the mTORC1 signaling pathway (Tabancay et al. (2003) J Biol Chem 278(41): 39921-39930), diminishes the stimulatory effect of Grb10 in β cell proliferation and insulin secretion. We believed that our study will provide important information on the mechanism of pancreatic β cell function and mTOR signaling, which could reveal new strategy and new drug targets for the clinical treatment of diabetes.