Kv2.1调控胰岛beta细胞凋亡机制研究及促胰岛beta细胞分泌和保护双功能高活性分子的发现

2型糖尿病是严重危害人类健康和生活质量的重大疾病，至今仍然缺乏安全有效的治疗药物。在2型糖尿病患者中有近65%的胰岛beta细胞受损，开发恢复功能性胰岛beta细胞药物作为治疗策略已是目前抗糖尿病药物发现的研究热点。Kv2.1属于电压门控钾离子通道家族，因其对胰岛beta细胞中葡萄糖刺激胰岛素分泌的重要调节作用备受重视。进一步研究还发现Kv2.1可以调控胰岛beta细胞的凋亡，但相关信号通路和机制尚未阐明。而且Kv2.1抑制剂应用于胰岛beta细胞保护的研究在国际上尚属起步阶段。因此，基于前期研究基础，本申请拟采用Kv2.1抑制剂作为小分子探针，深入探索Kv2.1调控胰岛beta细胞凋亡的分子事件，为Kv2.1发展成为抗2型糖尿病的新靶标提供理论依据。另外利用已建立的Kv2.1抑制剂筛选平台，开发具有促胰岛素分泌和保护胰岛beta细胞的双功能Kv2.1新型抑制剂用于抗2型糖尿病药物研究。

Type 2 diabetes is one of serious diseases harmful to human health and quality of life, but there is still lack of safe and effective drugs. As reported, ～65% deficit in beta cell mass appears in patients with type 2 diabetes. Therefore, to develop the drugs for restoring functional beta cell mass as treatment strategy is the current research focus. Kv2.1 belongs to voltage-gated potassium channel family and has pivotal role in regulation of glucose-induced insulin secretion. Moreover, it is also can regulate the apoptosis of beta cell, whereas the underlying mechanism and related signal pathways have never been fully explained and the research about applying Kv2.1 inhibitor to protect islet has just begun. Therefore, the purpose of this application is to explore the mechanism of Kv2.1 in the regulation of islet beta cell apoptosis with Kv2.1 inhibitor as probe, which might lay the foundation to develop Kv2.1 as new anti-diabetic target. Furthermore, the Kv2.1 novel inhibitor with dual function in promotion of insulin secretion and anti-apoptosis from Kv2.1 inhibitor screening platform may serve as a potential lead compound in the development of type 2 diabetes therapeutic drug.