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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060581-12
Application #
8463505
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Sato, Sheryl M
Project Start
2002-03-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
12
Fiscal Year
2013
Total Cost
$329,172
Indirect Cost
$115,424
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Maganti, Aarthi; Evans-Molina, Carmella; Mirmira, Raghavendra G (2014) From immunobiology to *-cell biology: The changing perspective on type 1 diabetes. Islets 6:
Mirmira, Raghavendra G (2014) Editorial: The vulnerable physician-scientist. Mol Endocrinol 28:603-6
Imam, Shahnawaz; Mirmira, Raghavendra G; Jaume, Juan C (2014) Eukaryotic translation initiation factor 5A inhibition alters physiopathology and immune responses in a "humanized" transgenic mouse model of type 1 diabetes. Am J Physiol Endocrinol Metab 306:E791-8
Hatanaka, Masayuki; Maier, Bernhard; Sims, Emily K et al. (2014) Palmitate induces mRNA translation and increases ER protein load in islet ?-cells via activation of the mammalian target of rapamycin pathway. Diabetes 63:3404-15
Oh, Eunjin; Stull, Natalie D; Mirmira, Raghavendra G et al. (2014) Syntaxin 4 up-regulation increases efficiency of insulin release in pancreatic islets from humans with and without type 2 diabetes mellitus. J Clin Endocrinol Metab 99:E866-70
Templin, Andrew T; Maier, Bernhard; Tersey, Sarah A et al. (2014) Maintenance of Pdx1 mRNA translation in islet ?-cells during the unfolded protein response. Mol Endocrinol 28:1820-30
Tersey, Sarah A; Maier, Bernhard; Nishiki, Yurika et al. (2014) 12-lipoxygenase promotes obesity-induced oxidative stress in pancreatic islets. Mol Cell Biol 34:3735-45
Evans-Molina, Carmella; Mirmira, Raghavendra G (2013) Achieving "PeaK-A" insulin secretion. Diabetes 62:1389-90
Evans-Molina, C; Hatanaka, M; Mirmira, R G (2013) Lost in translation: endoplasmic reticulum stress and the decline of *-cell health in diabetes mellitus. Diabetes Obes Metab 15 Suppl 3:159-69
Chen, Yi-Chun; Colvin, E Scott; Maier, Bernhard F et al. (2013) Mitogen-inducible gene 6 triggers apoptosis and exacerbates ER stress-induced *-cell death. Mol Endocrinol 27:162-71

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