菩人丹调控VHL/HIF信号通路抑制胰岛β细胞去分化的分子机制研究

胰岛β细胞去分化是除凋亡、自噬、增殖失败之外，导致2型糖尿病（T2DM）β细胞衰竭的又一个重要原因，也是T2DM形成的重要病理基础。新近研究发现：VHL/HIF信号通路介导的缺氧应激在β细胞去分化过程中扮演核心调控作用。课题组前期研究中发现：T2DM模型动物存在显著胰腺微循环障碍，β细胞氧供不足，β细胞形态、数量和功能受损。因此，本项目拟在前期工作的基础上，以缺氧—β细胞去分化—β细胞衰竭为新的研究切入点，以益气养阴、活血通络，改善胰腺微循环作用确切的中药复方菩人丹为研究载体，利用基因组学、生物信息学、分子生物学等现代技术方法，通过检测胰腺ATP水平、线粒体氧化酶活性、VHL/HIF信号通路及β细胞去分化相关功能指标变化，揭示菩人丹改善胰腺微循环、抑制缺氧所致β细胞去分化的分子机制，提出并验证假说：改善β细胞缺氧损伤状态，阻止β细胞去分化，是改善T2DM胰岛素分泌和维持机体糖稳态的新策略。

Diabetes is associated with β-cell failure, which including β-cell dysfunction and reduced β-cell mass, and β-cell dedifferentiation is an emerging concept that might account for both of them. Hypoxic stress is one of the incentives of β-cell dedifferentiation. It has been confirmed that PuRenDan could improve microcirculation of pancreas in T2DM and then renovate β-cell mass and function. In this research, db/db mice will be used as the diabetic model to investigate PuRenDan’s effects on ATP levels, mitochondrial oxidase activity, VHL/HIF signaling pathway and functional parameters of β-cell dedifferentiation by genomics, bioinformatics and Molecular biology technology, thus revealing the molecular mechanisms of PuRenDan on β-cell dedifferentiation, and verifying the hypothesis: renovating pancreatic microcirculation can improve extracellular environment of β-cell, alleviate anoxic injury, and then inhibit β-cell dedifferentiation, which is a new strategy of maintaining glucose homeostasis.