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 #
5R37DK042394-15
Application #
8138411
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
1998-01-01
Project End
2012-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
15
Fiscal Year
2011
Total Cost
$498,843
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Han, Jaeseok; Kaufman, Randal J (2017) Physiological/pathological ramifications of transcription factors in the unfolded protein response. Genes Dev 31:1417-1438
Yao, Ting; Deng, Zhuo; Gao, Yong et al. (2017) Ire1? in Pomc Neurons Is Required for Thermogenesis and Glycemia. Diabetes 66:663-673
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
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
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
Han, Jaeseok; Kaufman, Randal J (2016) The role of ER stress in lipid metabolism and lipotoxicity. J Lipid Res 57:1329-38
Bai, Yongsheng; Kinne, Jeff; Donham, Brandon et al. (2016) Read-Split-Run: an improved bioinformatics pipeline for identification of genome-wide non-canonical spliced regions using RNA-Seq data. BMC Genomics 17 Suppl 7:503
Placzek, Andon N; Prisco, Gonzalo Viana Di; Khatiwada, Sanjeev et al. (2016) eIF2?-mediated translational control regulates the persistence of cocaine-induced LTP in midbrain dopamine neurons. Elife 5:
Wang, Miao; Kaufman, Randal J (2016) Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature 529:326-35

Showing the most recent 10 out of 106 publications