蛋白激酶D1通过泛素蛋白酶体途径降解SIRT5的分子机制及对胰岛β细胞衰老的影响

氧化应激及炎症是导致胰岛β细胞衰老及糖尿病发生的重要原因。我们既往的研究表明蛋白激酶D1（PKD1）在活性氧刺激下可诱导炎症因子分泌，促进成纤维细胞衰老，但其是否调控β细胞衰老及糖尿病发生仍不清楚。我们的预实验显示：高糖激活的PKD1可通过E3泛素连接酶NEDL2降解SIRT5，导致β细胞衰老。PKD抑制剂干预db/db小鼠12周可以明显抑制β细胞衰老，降低空腹血糖等。据此我们假设：高糖激活的PKD1可促进SIRT5降解，导致β细胞衰老及糖尿病发生。本项目拟首先在分子细胞水平探讨高糖诱导PKD1通过蛋白酶体途径降解SIRT5的机制及对β细胞衰老的影响；进而在db/db及β细胞特异性PKD1基因敲除小鼠诱导的2型糖尿病模型中，研究抑制或沉默PKD1对β细胞衰老及糖代谢的影响。本项目将揭示PKD1-SIRT5信号通路在高糖诱导的β细胞衰老及糖尿病发生中的作用，为糖尿病防治提供新的思路和靶点。

Oxidative stress and inflammation are important causes of the senescence of prancreatic β cells and diabetes.Our previous studies have shown that protein kinase D1 (PKD1) can induce the secretion of inflammatory factors and promote the senescence of fibroblasts under the stimulation of reactive oxygen species, but whether it regulates the senescence of β cells and the occurrence of diabetes remains unclear.Our preliminary experiments showed that PKD1 activated by high glucose can degrade SIRT5 through E3 ubiquitin ligase NEDL2, leading to the senescence of β cells. PKD inhibitor intervention in db/db mice for 12 weeks can significantly inhibit the senescence of β cells and reduce fasting blood glucose.Therefore, we hypothesized that high glucose activated PKD1 can promote the degradation of SIRT5, leading to the senescence of β cells and the occurrence of diabetes.This project intends to first explore the mechanism of high glucose induced PKD1 degradation of SIRT5 through the proteasome pathway at the molecular and cellular level and the effect on the senescence of β cells.Furthermore, the effects of inhibition or silencing of PKD1 on the senescence and glucose metabolism of β cells were studied in type 2 diabetes model db/db and β cell-specific PKD1 gene knockout mice induced type 2 diabetes model.This project will reveal the role of PKD1-SIRT5 signaling pathway in the senescence of β cells induced by high glucose and the occurrence of diabetes, and provide new ideas and targets for the prevention and treatment of diabetes.