KDM2A调节胰岛β细胞的衰老 vs. 凋亡平衡的机制研究

一般认为细胞衰老是T2D的高危因素。申报者前期发现老年与肥胖小鼠的胰岛高表达KDM2A，诱导敲除胰岛β细胞KDM2A仅4周后，肥胖小鼠胰岛细胞衰老减轻，但凋亡却增加，葡萄糖刺激胰岛素分泌功能严重受损。已知KDM2A参与调控细胞增殖与肿瘤细胞侵袭，而β细胞是典型的长寿命、慢增殖细胞，有研究显示衰老可增强其分泌功能。因此假设衰老是β细胞主动代偿胰岛素抵抗的机制，KDM2A调控β细胞的衰老vs.凋亡平衡，使其在胰岛素抵抗的应激条件下，促β细胞衰老，抵抗凋亡，维持分泌功能。我们拟利用单细胞转录组测序技术，连续动态的检测β细胞敲除后的单细胞转录组变化，然后以胰岛β细胞指数、衰老指数、SASP指数及凋亡指数对其进行生物信息学分析，解析KDM2A调控β细胞衰老、凋亡及胰岛素功能及相关信号通路间的相互作用与机制，并在蛋白表达及体外细胞学机制两个层面进行验证，最终阐明胰岛β细胞通过衰老阻止T2D进展的机制。

It is generally believed that cellular senescence is a high risk factor of T2D. However, we found in the previous study that KDM2A was highly expressed in the islets of the aged and obese mice. The glucose-stimulated insulin secretion (GSIS) obviously reduced in only 4 weeks after kdm2a was induced to knock out in the islet β cells, and the cellular senescence was blocked, apoptosis was increased. It is known that KDM2A is involved in the regulation of cell proliferation and tumor cell invasion, while β cell is a typical long-lived and slow proliferating cell. Some studies have shown that the cellular senescence of β cell can enhance its secretory function. Therefore, we hypothesized that cellular senescence is a mechanism by which β cells actively compensate for insulin resistance. KDM2A regulates the balance of cellular senescence vs. apoptosis of β cells. so that KDM2A overexpression can promote the cellular senescence of β cell under the stress of insulin resistance, which make the β cell have ability to resist the apoptosis to maintain its insulin secretory function. We intend to 10× Genomics single cell transcriptome sequencing technology to continuously and dynamically detect the changes of single cell transcriptome after β cell KDM2A knockout, and then apply bioinformatics analysis on β cell index, senescence index, SASP index and apoptosis index to dissect the mechanism of KDM2A regulating β cell senescence, apoptosis, insulin function and related signal pathways. Finally we will verify the mechanisms found in the single cell transcriptome sequencing and bioinformatics analysis to fully dissect the mechanism of preventing T2D progression by cellular senescence of islet β cell.