The cumulative prevalence of diabetes and pre-diabetes in the US is now a staggering 40%. Deficiencies of islet ? cell mass and/or function are paramount in the transition from impaired glucose tolerance to frank diabetes in virtually all forms of diabetes, and such deficiencies emanate from pathways contributing to inflammatory, ER, and oxidative stress among others. In this renewal application, we will focus on a novel pathway we identified during the past funding cycle that appears to regulate the translational responses to stress in the ? cell. Eukaryotic translation initiation factor 5A (eIF5A) and its rate-limiting modifying enzyme deoxyhypusine synthase (DHS) are highly conserved proteins that, together, are responsible for the shuttling and translational elongation of specific inflammation- and ER stress-induced transcripts in ? cells. Strikingly, it appears that eIF5A depends exclusively upon DHS for its crucial post-translational modification (known as hypusination) and, reciprocally, the only known substrate for DHS is eIF5A. We believe DHS and eIF5A function together in a pathway that regulates the balance between the translation of emergency proteins for the adaptive response to stress, and the translation of proteins that initiate cellular execution when stress proceeds unabated. We hypothesize that ? cell stress pathways in type 2 diabetes are promoted at the translational elongation level by the actions of DHS and eIF5A. We believe, as a research group, we are uniquely positioned with the biochemical and islet expertise, and a comprehensive set of reagents--including conventional and conditional KO mice, in vivo RNA interference technologies--to test this hypothesis. We propose the following 3 integrated aims:
Aim 1 : Identify the molecular mechanisms by which DHS/eIF5A promotes the production of stress- responsive proteins in islet ? cells.
Aim 2 : Determine the regulatory mechanisms underlying the reciprocal compartmentation of DHS and eIF5A in ? cells during acute stress.
Aim 3 : Determine the role of DHS/eIF5A in islet compensation and dysfunction in mouse models of diabetes and inflammation. We believe the major impact of these studies will be to establish a fundamental new post-transcriptional paradigm in the study of inflammatory and ER stress responses that may be applicable in a wide variety of cell types relevant to diabetes pathogenesis.
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