Role of the RNA-binding, polyC-binding proteins in pancreatic beta cells

胰腺β细胞分泌的胰岛素不足是所有形式糖尿病的基础。在2型糖尿病(T2D)中， β细胞衰竭至少部分是由长期的氧化和内质网应激引起的，这导致胰岛素受损 分泌、细胞凋亡和细胞特性丧失。因此，阐明β的分子机制 细胞应激反应是开发新的治疗策略的核心。MRNA的调控 翻译是细胞对应激反应中一个关键且高度保守的组成部分。β细胞是 特别依赖于翻译控制，然而在β细胞中控制翻译的因素在很大程度上 未被开发的。通过关注翻译调控，我们已经确定了RNA的PolyC结合蛋白家族 由PCBPs1-4和hnRNPk组成的结合蛋白(RBPs)是转录后反应中的重要角色 胰岛β细胞的调控格局。我们已经在β细胞中阐明了一个新的hnRNPK/JUND通路 这会影响代谢应激期间的氧化还原动态平衡和细胞活性。此外，我们发现PCBP 1和 2转录后调节Nkx2.2，可能促进β细胞特性，抑制交替内分泌 细胞的命运。重要的是，我们发现的基本方面已经在原代小鼠身上得到了体外验证。 来自野生型和db/db小鼠的胰岛以及人类的胰岛。我们假设通过减轻压力来维持β 细胞鉴定和存活具有巨大的治疗潜力，将与 具体目的如下：(1)阐明PCBP 1和2在β细胞中的体内作用，(2) 确定hnRNPk在应激过程中如何影响β细胞的翻译格局，以及(3)建立 限制性商业惯例多聚C结合蛋白家族与人胰岛β细胞特性、功能和功能的相关性 生死存亡。尽管雄心勃勃，但考虑到我们的经验和我们的制度，这些实验是可行的 环境。对这一RBPs家族在胰岛β细胞中作用的新认识 它们调节胰岛素分泌和机体葡萄糖稳态的机制将会阐明很多。 糖尿病的治疗需要新的靶点。

Insufficient secretion of insulin from pancreatic β cells underlies all forms of diabetes. In type 2 diabetes (T2D), β cell failure is caused at least in part by prolonged oxidative and ER stress, which leads to impaired insulin secretion, apoptosis, and loss of cell identity. Thus, elucidating the molecular mechanisms comprising the β cell stress response is central to the development of novel therapeutic strategies. Regulation of mRNA translation is a critical and highly conserved component of the cellular response to stress. β cells are particularly dependent on translational controls, yet the factors controlling translation in β cells are largely unexplored. By focusing on translational regulation, we have identified the polyC binding protein family of RNA binding proteins (RBPs) comprising PCBPs1-4 and hnRNPk as important players in the post-transcriptional regulatory landscape of pancreatic beta cells. We have elucidated a novel hnRNPK/JunD pathway in β cells that influences redox homeostasis and cell viability during metabolic stress. Further, we find that PCBPs 1 and 2 post-transcriptionally regulate Nkx2.2, likely promoting beta cell identity and repressing alternate endocrine cell fates. Importantly, fundamental aspects of our findings have been validated ex vivo in primary mouse islets from wild-type and db/db mice and in human islets. We hypothesize that reducing stress to maintain β cell identity and survival has great therapeutic potential and will comprehensively explore this pathway with the following specific aims: (1) To elucidate the in vivo roles exerted by PCBPs 1 and 2 in beta cells, (2) to determine how hnRNPk influences the translational landscape of beta cells during stress, and (3) to establish the relevance of the polyC binding protein family of RBPs to human islet beta cell identity, function and survival. While highly ambitious, these experiments are feasible given our experience and our institutional environment. The new understanding of the roles of this family of RBPs in pancreatic beta cells and the mechanisms by which they regulate insulin secretion and organismal glucose homeostasis will elucidate much needed new targets for the therapy of diabetes.