Lnc RNA 对Beta－arrestin2信号通路介导的胰岛β细胞容量调控作用研究

胰岛β细胞数量/容量(mass)不足导致胰岛素分泌不能满足外周组织需求是2型糖尿病发生和发展的关键因素。促进β细胞增殖、维持β细胞功能完整是亟待解决的问题。申请人前期研究发现β细胞内的beta-arrestin2表达在高脂状态下减少。敲除beta-arrestin2小鼠葡萄糖刺激的胰岛素分泌减退，β细胞mass减少。此外,我们还发现β细胞内存在有与Arrb2基因上游潜在结合的lncRNA。提示beta-arrestin2是β细胞重要调控因子，并可能受lncRNA调控。在此基础上，本申请拟从分子、细胞、组织和动物层面，以beta-arrestin2为着眼点，探讨其影响β细胞mass的分子调控机制，揭示胰岛β细胞mass从正常糖代谢到糖尿病进程中的变化规律，以及目标lncRNA对Arrb2的调控作用。研究结果将为探讨β细胞生存调节提供新理论基础，为糖尿病的防治提供潜在干预靶点和手段。

Pancreatic β-cell failure induced by loss of functional β-cell mass to compensate peripheral insulin needs is a hallmark of type 2 diabetes. Identification of key signal molecules involved in regulating β-cell function and mass is thus essential to underpin the development of novel pharmacological approaches to the treatment of type 2 diabetes. We found in previous studies that expression of beta-arrestin2, an adapter protein, decreased in islets from mice fed with high fat diet. Beta-arrstin2 knockout mice presented with impaired glucose-stimulated insulin secretion from a hyperglycemic clamp test and decreased in β-cell mass in mice fed with high fat diet, suggesting a role of beta-arrestin2 in regulation of β-cells. Moreover, β-cell expresses several lncRNAs which had potential binding sites within 2000bp upstream of Arrb2, suggesting a role of the lncRNAs on beta-arrestin2 regulation. The present program will focus on exploring the molecular mechanisms by which beta-arrestin2 regulates β-cell mass, how β-cell mass changes during the development of type 2 diabetes, and exploring if the target lncRNA regulates Arrb2 expression. The completion of these studies will shed light on our understanding the mechanisms involved in the regulation of β-cell mass by beta-arrestin2, and the regulation of Arrb2 expression by the lncRNA. We believe it is critical for developing therapeutic interventions to the prevention of diabetes.