Transcriptional and Translational Mechanisms Governing Beta Cell Function
PROJECT SUMMARY/ABSTRACT The prevalence of diabetes and pre-diabetes in the US is now a staggering 51%. It has become increasingly clear that development of both type 1 and type 2 diabetes depends upon the ability or inability of the islet ? cell to adapt to prevailing stresses in either disease. Elucidating the molecular mechanisms of the ? cell response in diabetes has remained a long-standing objective of this R01 award over the years. My laboratory has recently focused on defining how mRNA translation in the ? cell is regulated in response to diabetogenic stresses. The translation factor eIF5A functions as an acute response factor in the ? cell that either activates translation of specific mRNAs, enabling the requisite cellular response. Notably, eIF5A is the only protein containing the unique amino acid hypusine. When ?hypusinated,? eIF5A permits translation of specific mRNAs; when ?unhypusinated,? eIF5A is dysfunctional. The formation of hypusine is governed by two rate-limiting enzymes, ornithine decarboxylase (ODC) and deoxyhypusine synthase (DHS). ODC generates intracellular polyamines from ornithine, and DHS utilizes the polyamine spermidine to form hypusine on eIF5A. Because polyamines and hypusine can be manipulated by diet or clinically available small molecule inhibitors, they represent real-world targets to intervene in human diabetes pathogenesis. This application takes a distinctly disease-specific approach to understand better the role of the polyamine/hypusine pathway in type 1 and type 2 diabetes. We hypothesize that the pathway that generates polyamines and hypusine integrates extracellular diabetogenic signals to promote stress-specific mRNA translation in the islet ? cell. We believe we are uniquely positioned with the expertise in ? cell biology and mRNA translation and with unique reagents?? including novel conditional KO mice, mRNA translation assessment tools, and access to clinical trial samples? ?to test this hypothesis. We propose the following 3 aims Aim 1: Interrogate the mechanism by which the polyamine/hypusine pathway contributes to the translation of specific mRNAs in islet ? cells. Aim 2: Determine the adaptive and maladaptive roles of the polyamine/hypusine pathway in ? cell compensation and dysfunction, respectively, in insulin resistance. Aim 3: Define the roles of hypusine and polyamines during the pathogeneses of mouse and human type 1 diabetes. We believe the major impact of these studies will be to identify a new tractable pathway that contributes to the adaptive and maladaptive responses of the ? cell to inflammatory, ER, and oxidative stresses. Because manipulation of this pathway is achievable with small molecule inhibitors, these studies will provide the first evidence for the feasibility of these inhibitors in the treatment of diabetes.