多功能核蛋白PSF在2型糖尿病胰岛β细胞功能保护中的作用及机制研究

胰岛β细胞功能缺陷是2型糖尿病的两个主要原因之一，我们的前期研究发现，多功能核蛋白PSF在保护胰岛β细胞，避免β细胞发生功能障碍中起到重要作用，表现为：2型糖尿病小鼠胰岛β细胞中PSF表达显著下降，而在疾病早期，借助于腺相关病毒（AAV）胰腺导管注射回复β细胞PSF表达，可有效改善2型糖尿病小鼠出现的胰岛素分泌功能障碍、空腹血糖升高以及糖耐量受损。进一步研究发现，PSF在胰岛β细胞正常功能的维持中具有至关重要的作用，其表达水平的下降极有可能通过上调乳酸脱氢酶Ldha等的基因表达导致β细胞功能缺陷，但具体机制尚不明确。本研究的目的，是借助胰岛灌注、膜片钳等胰岛β细胞功能研究的方法，以及染色质免疫共沉淀等分子生物学技术和高通量测序等组学实验，在分子、细胞和动物水平探讨PSF对胰岛β细胞功能的调控作用及机制。本研究的完成不仅能在理论上丰富2型糖尿病的发病机制，并可能为临床新疗法提供实验证据。

Several studies have revealed that pancreatic β cell failure is core of type 2 diabetes mellitus (T2DM). According to our previous studies, multifunctional nuclear protein PSF played an important role in the maintenance of β cell homeostasis. PSF expression in the β cells of db/db mice decreased significantly, while in the early stage of T2DM, PSF replenishment via pancreatic duct of adeno-associated virus (AAV) infection effectively improved defected insulin secretion, elevated fasting blood glucose and impaired glucose tolerance in db/db mice. Further studies showed that PSF was essential for normal β cell function, and it was highly possible that decreased PSF lead to β cell dysfunction by up-regulating LdhA gene expression, but the specific mechanism is still unclear. The purpose of this study is to explore the regulatory effect of PSF on β cell function in vitro or in vivo by means of the methods of islet perfusion, patch clamp, ChIP, RNA-sequencing, etc. The study will not only theoretically enrich the pathogenesis of T2DM, but also provide experimental evidence for new clinical therapies.