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.
Diabetes is a disorder of insulin-producing and insulin-responsive cells that afflicts 24 million Americans, and its incidence is rising at an alarming rate. The specific goal of this grant is to investigate how the islet ? cell responds to stress, as seen in diabetes, at the mRNA translational level. Overall, this project seeks to understand how ? cells function to release insulin and how specific proteins allow for ? cells to respond appropriately or inappropriately to stress, with the hope that manipulating such proteins might lead to new therapy for diabetes.
|Xiong, Xiwen; Wang, Gaihong; Tao, Rongya et al. (2016) Sirtuin 6 regulates glucose-stimulated insulin secretion in mouse pancreatic beta cells. Diabetologia 59:151-60|
|Mirmira, Raghavendra G; Sims, Emily K; Syed, Farooq et al. (2016) Biomarkers of Î²-Cell Stress and Death in Type 1 Diabetes. Curr Diab Rep 16:95|
|Maganti, Aarthi V; Tersey, Sarah A; Syed, Farooq et al. (2016) Peroxisome Proliferator-activated Receptor-Î³ Activation Augments the Î²-Cell Unfolded Protein Response and Rescues Early Glycemic Deterioration and Î² Cell Death in Non-obese Diabetic Mice. J Biol Chem 291:22524-22533|
|Villa, Stephanie R; Priyadarshini, Medha; Fuller, Miles H et al. (2016) Loss of Free Fatty Acid Receptor 2 leads to impaired islet mass and beta cell survival. Sci Rep 6:28159|
|Takatani, Tomozumi; Shirakawa, Jun; Roe, Michael W et al. (2016) IRS1 deficiency protects Î²-cells against ER stress-induced apoptosis by modulating sXBP-1 stability and protein translation. Sci Rep 6:28177|
|Shih, Han; Mirmira, Raghavendra G; Lin, Chien-Chi (2015) Visible light-initiated interfacial thiol-norbornene photopolymerization for forming islet surface conformal coating. J Mater Chem B Mater Biol Med 3:170-175|
|Mastracci, Teresa L; Robertson, Morgan A; Mirmira, Raghavendra G et al. (2015) Polyamine biosynthesis is critical for growth and differentiation of the pancreas. Sci Rep 5:13269|
|Maganti, Aarthi V; Maier, Bernhard; Tersey, Sarah A et al. (2015) Transcriptional activity of the islet Î² cell factor Pdx1 is augmented by lysine methylation catalyzed by the methyltransferase Set7/9. J Biol Chem 290:9812-22|
|Filgueiras, Luciano Ribeiro; Brandt, Stephanie L; Wang, Soujuan et al. (2015) Leukotriene B4-mediated sterile inflammation promotes susceptibility to sepsis in a mouse model of type 1 diabetes. Sci Signal 8:ra10|
|Priyadarshini, Medha; Villa, Stephanie R; Fuller, Miles et al. (2015) An Acetate-Specific GPCR, FFAR2, Regulates Insulin Secretion. Mol Endocrinol 29:1055-66|
Showing the most recent 10 out of 67 publications