Grb10蛋白调控衰老和糖尿病胰岛β细胞去分化的机制研究

Pancreatic β cell senescence leads to decreased function and impaired secretion, which seriously affect the health span of humans. A comprehensive understanding of the mechanism of pancreatic β-cell aging is important for the prevention and treatment of serious aging-associated diseases such as type 2 diabetes, and has a very important scientific and clinical significance for promoting health and longevity. Recent studies have shown that dedifferentiation of β cells is very important for the secretion of insulin. However, the underlying mechanisms remain unclear. Growth Factor Receptor-Bound Protein 10 (Grb10) is an adaptor protein that regulates insulin and mTORC1 signaling pathway. Our preliminary data showed that ablation of Grb10 in pancreatic β cells decreased pancreatic β cell dedifferentiation. In this project, we will use pancreatic β cell-specific Grb10 knockout/overexpression mouse models and β cell lines, as well as human islets to systematically study the function that Grb10 regulates β cell dedifferentiation from three different levels of body, cells and molecules, and to elucidate new mechanisms for the regulation of pancreatic β-cell dedifferentiation. We believe that our study will provide important information on the regulation of pancreatic β cell function, which could reveal potential new strategies and new drug targets for the clinical prevention and treatment of diabetes and pancreatic β-cell aging.

胰岛β细胞衰老导致功能下降及胰岛素分泌障碍，严重影响人们的健康寿命。全面了解β细胞老化的机制对于防治衰老导致的重大代谢性疾病（如2型糖尿病），促进人们健康长寿有着非常重要的科学和临床意义。最近研究表明β细胞去分化对于胰岛素分泌具有十分重要的作用。然而β细胞去分化机制仍不清楚。Grb10(Growth Factor Receptor-Bound Protein 10)是一个调节胰岛素和mTORC1信号通路的配体蛋白。我们前期数据显示在β细胞中敲除Grb10基因抑制细胞去分化。本研究在国内外首次利用胰岛β细胞特异性Grb10敲除(bGrb10KO)和过表达（bGrb10Tg）小鼠模型及独特的Grb10敲除/过表达β细胞模型和人胰岛模型，从在体、细胞和分子三个不同层面系统研究Grb10对β细胞功能调控，阐明β细胞去分化调控新机制，为预防胰岛β细胞老化，治疗糖尿病，延长健康寿命提供新靶点和思路。

胰岛β细胞衰老导致功能下降及胰岛素分泌障碍，严重影响人们的健康寿命。全面了解β细胞老化的机制对于防治衰老导致的重大代谢性疾病（如2型糖尿病），促进人们健康长寿有着非常重要的科学和临床意义。最近研究表明β细胞去分化对于胰岛素分泌具有十分重要的作用。然而β细胞去分化机制仍不清楚。Grb10(Growth Factor Receptor-Bound Protein 10)是一个调节胰岛素和mTORC1信号通路的配体蛋白。我们前期数据显示在β细胞中敲除Grb10基因抑制细胞去分化。本研究在国内外首次利用胰岛β细胞特异性Grb10敲除(bGrb10KO)和过表达（bGrb10Tg）小鼠模型及独特的Grb10敲除/过表达β细胞模型和人胰岛模型，从在体、细胞和分子三个不同层面系统研究Grb10对β细胞功能调控，阐明β细胞去分化调控新机制，完成了以下三方面：（1）研究胰岛β细胞特异性 Grb10 基因敲除/过表达小鼠模型，阐明 Grb10 对衰老或代谢应激条件下去分化的影响及相关机制；（2）阐明 Grb10 基因调控胰岛β细胞去分化的具体分子机制；（3）发现Grb10 对人胰岛β细胞去分化的影响。为预防胰岛β细胞老化，治疗糖尿病，延长健康寿命提供新靶点和思路。