Insufficient secretion of insulin from pancreatic ? cells underlies all forms of diabetes. In type 2 diabetes (T2D), ? 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 ? 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. ? cells are particularly dependent on translational controls, yet the factors controlling translation in ? 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 ? 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 ? 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.
Failure of pancreatic ? cells underlies the progression of all forms of diabetes. The proposed work relies on cutting edge proteomic, genomic and genetic approaches to elucidate the function, components and targets of a new stress responsive translational pathway, the results of which have the potential to identify new nodes for intervention to prevent or delay the onset of diabetes.
