PTP-PEST在胰岛素分泌和胰岛B细胞凋亡中的作用及分子机制

蛋白酪氨酸磷酸酶（PTP）是重要的细胞调控因子，与胰岛细胞增殖凋亡、胰岛素抵抗和胰岛素分泌等生理过程密切相关。PTP-PEST在多种生理活动中至关重要，其全身基因敲除小鼠致死，但其在糖脂代谢和胰岛细胞中的功能知之甚少。我们应用胰岛B细胞特异性敲除PTP-PEST基因小鼠和其特异性小分子抑制剂的前期实验结果表明：PTP-PEST调控葡萄糖诱导的胰岛素分泌和高脂诱导的胰岛B细胞凋亡；同时其磷酸酶活力和蛋白水平也受到高糖/高脂的调节。理解PTP-PEST在胰岛细胞中的功能及作用机制，具有重要科学意义。基于这些研究基础，本课题将联合动物实验，细胞电生理学、分子与细胞生物学和生化酶学等方法，阐明PTP-PEST在调控胰岛素分泌和胰岛B细胞凋亡中的作用及分子基础，尤其是PTP-PEST对胰岛B细胞中的钙信号和对PDK1-AKT信号途径的调控机理，以及PTP-PEST在胰岛B细胞中受调控的分子机制。

Protein tyrosine phosphatases(PTPs) are important regulators, participating in islet cell proliferation and apoptosis,、insulin resistance and insulin secretion. PTP-PEST play vital roles in many physiological processes, and PTP-PEST knockout mice are lethal; however, its function in glucose/lipid metabolism or pancreatic beta cells are largely unknown. Recently, our beta-cell-specific knockout mice had impared glucose tolerance and glucose stimulated insulin secretion; Experimental results by application of PTP-PEST specific inhibitor or PTP-PEST RNA interfere support the functional importance of PTP-PEST in insulin secretion and beta cell apoptosis. PTP-PEST are also regulated in pancreatic beta cell upon glucose and/or fatty acid stimulation. Therefore, elucidation of PTP-PEST in pancreatic beta cell and the underlying mechanisms have great scientific values. In this study, we are going to explore the PTP-PEST function and its regulation in pancreatic beta cells and their detailed molecular mechnisms, by combination of animal studies、 electrophysiological and biochemical techniques.