Diabetes is a world-wide major cause of morbidity and mortality that is associated with disturbances in ? cell function that result in the loss of glucose-stimulated insulin secretion for control of blood glucose. Recent studies demonstrated an association between ? cell function and/or survival with an intracellular signaling pathway termed the unfolded protein response (UPR). Upon accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER), three UPR signal transduction subpathways are activated to increase the protein folding capacity and increase the protein degradative machinery. Protein synthesis is transiently attenuated through PERK-mediated phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (elF2a), one subpathway of the UPR. Recently, we discovered that PERK/elFa signaling is required to preserve the environment of the ER to support high-level insulin production in response to increases in blood glucose. Our discoveries support the hypothesis that increases in insulin production exceed the protein-folding capacity of the ER. Under these conditions, the PERK/elF2a subpathway is activated transiently to prevent oxidative stress, and when perpetually activated, induces a cell death response through induction of the transcription factor CHOP. We propose that reducing oxidative stress or preventing CHOP expression will improve ? cell function and survival in response to insulin resistance. Given the significance of the PERK/elF2a UPR subpathway in ? cell function, is it likely that IRE1 and ATF6 UPR subpathways are also essential for ? cell function. The studies proposed will elucidate the requirements of PERK/elF2a, IRE1, and ATF6 signaling using novel genetic mouse models in which UPR sensor genes can be turned 'on'or 'off'in a temporal- and/or tissue-specific manner. These in vivo models will be used to elucidate novel insights into ? cell failure and to evaluate novel modalities for therapeutic intervention. Diabetes is a multifactorial disease that stems largely from an inability of pancreatic ? cells to produce adequate amounts of insulin for control of blood glucose levels. Excessive insulin synthesis can lead to accumulation of unfolded protein within the ? cell. The study of cell signaling pathways activated by unfolded protein will lead to insights and new treatments for this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DK042394-13
Application #
7910701
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
1998-01-01
Project End
2011-06-30
Budget Start
2010-09-01
Budget End
2011-06-30
Support Year
13
Fiscal Year
2010
Total Cost
$385,751
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biochemistry
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zhang, Shuping; Macias-Garcia, Alejandra; Velazquez, Jason et al. (2018) HRI coordinates translation by eIF2?P and mTORC1 to mitigate ineffective erythropoiesis in mice during iron deficiency. Blood 131:450-461
Wang, Jie-Mei; Qiu, Yining; Yang, Zhao et al. (2018) IRE1? prevents hepatic steatosis by processing and promoting the degradation of select microRNAs. Sci Signal 11:
Yao, Ting; Deng, Zhuo; Gao, Yong et al. (2017) Ire1? in Pomc Neurons Is Required for Thermogenesis and Glycemia. Diabetes 66:663-673
Choi, Woo-Gyun; Han, Jaeseok; Kim, Ji-Hyeon et al. (2017) eIF2? phosphorylation is required to prevent hepatocyte death and liver fibrosis in mice challenged with a high fructose diet. Nutr Metab (Lond) 14:48
DeZwaan-McCabe, Diane; Sheldon, Ryan D; Gorecki, Michelle C et al. (2017) ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis. Cell Rep 19:1794-1806
Han, Jaeseok; Kaufman, Randal J (2017) Physiological/pathological ramifications of transcription factors in the unfolded protein response. Genes Dev 31:1417-1438
Poothong, Juthakorn; Sopha, Pattarawut; Kaufman, Randal J et al. (2017) IRE1? nucleotide sequence cleavage specificity in the unfolded protein response. FEBS Lett 591:406-414
Jin, Jung-Kang; Blackwood, Erik A; Azizi, Khalid et al. (2017) ATF6 Decreases Myocardial Ischemia/Reperfusion Damage and Links ER Stress and Oxidative Stress Signaling Pathways in the Heart. Circ Res 120:862-875
Poothong, Juthakorn; Tirasophon, Witoon; Kaufman, Randal J (2017) Functional analysis of the mammalian RNA ligase for IRE1 in the unfolded protein response. Biosci Rep 37:
Chiang, Wei-Chieh; Chan, Priscilla; Wissinger, Bernd et al. (2017) Achromatopsia mutations target sequential steps of ATF6 activation. Proc Natl Acad Sci U S A 114:400-405

Showing the most recent 10 out of 112 publications