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

胰腺β细胞分泌胰岛素不足是所有形式糖尿病的基础。在2型糖尿病（T2 D）中， β细胞衰竭至少部分是由长期的氧化和ER应激引起的，这导致胰岛素受损。 分泌、凋亡和细胞特性丧失。因此，阐明β-淀粉样蛋白的分子机制， 细胞应激反应是开发新的治疗策略的核心。调节mRNA 翻译是细胞对应激反应的关键和高度保守的组成部分。β细胞是 特别是依赖于翻译控制，但β细胞中控制翻译的因素在很大程度上是 未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 包含PCBP 1 -4和hnRNPk的结合蛋白（RBP）作为转录后调控的重要参与者， 胰腺β细胞的调节景观。我们已经阐明了β细胞中一种新的hnRNPK/JunD通路 在代谢应激期间影响氧化还原稳态和细胞活力。此外，我们发现PCBPs 1和 2转录后调节Nkx2.2，可能促进β细胞身份并抑制替代内分泌 细胞命运重要的是，我们发现的基本方面已经在原代小鼠中离体验证， 来自野生型和db/db小鼠的胰岛和人胰岛。我们假设减少压力以维持β 细胞身份和存活具有巨大的治疗潜力，并将全面探索这一途径， 以下具体目标：（1）阐明PCBPs 1和2在β细胞中发挥的体内作用，（2） 确定hnRNPk如何影响压力期间β细胞的翻译景观，以及（3）建立 RBP的polyC结合蛋白家族与人胰岛β细胞特性、功能和 生存这些实验虽然雄心勃勃，但鉴于我们的经验和我们的体制， 环境对这个RBP家族在胰腺β细胞中的作用的新认识， 它们调节胰岛素分泌和机体葡萄糖稳态的机制将阐明许多 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.