Client proteins of the secretory pathway fold to their native structures in the endoplasmic reticulum (ER) through reactions that are catalyzed by chaperones, oxidoreductases, and other protein-modifying enzymes. However, under high secretory demand these ER-resident activities become overwhelmed, leading client proteins to accumulate in unfolded forms within the ER. This condition-termed ER stress-puts affected cells at increased risk for death. As such, unchecked ER stress is now recognized as being central to the development of various human diseases of cell loss, including neurodegeneration and Type 2 diabetes. Unfolded proteins in the ER trigger signaling pathways called the unfolded protein response (UPR). Under remediable levels of ER stress, the UPR sets in motion transcriptional and translational changes that promote adaptation. But when confronted with irremediable levels of ER stress, these adaptive measures fail and the UPR instead switches strategies to trigger programmed cell death-we refer to this outcome as the terminal UPR. Our overall goal for this R01 is twofold: (1) elucidate underlying molecular mechanisms through which the terminal UPR and oxidative stress synergize to cause pancreatic ?-cell degeneration, and (2) therapeutically target key nodes in the terminal UPR to protect against mouse models of diabetes. The elucidation of mechanisms connecting ER and oxidative stress signaling components holds the promise of developing novel drugs to treat diverse cell degenerative diseases, including diabetes.

Public Health Relevance

When the insulin-producing cells of our pancreas are overworked trying to control blood sugar levels, these cells can become injured and activate an internal suicide program. Diabetes results when too many insulin- producing cells die. In this proposal, we explore a novel strategy to protect these cells from injury by blocking their internal suicide program, which if successful may lead to new drugs to treat diabetes in people.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK095306-01A1
Application #
8505075
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
2013-08-01
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
1
Fiscal Year
2013
Total Cost
$380,927
Indirect Cost
$138,427
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Hiniker, Annie; Oakes, Scott A; Rao, Rajesh C (2017) Bilateral Choroidal Metastases from Pancreatic Adenocarcinoma. Ophthalmology 124:1825
Moore, Paul C; Oakes, Scott A (2017) CPEB4 links the clock and the UPR to protect the liver. Nat Cell Biol 19:79-81
Morita, Shuhei; Villalta, S Armando; Feldman, Hannah C et al. (2017) Targeting ABL-IRE1? Signaling Spares ER-Stressed Pancreatic ? Cells to Reverse Autoimmune Diabetes. Cell Metab 25:883-897.e8
Feldman, Hannah C; Tong, Michael; Wang, Likun et al. (2016) Structural and Functional Analysis of the Allosteric Inhibition of IRE1? with ATP-Competitive Ligands. ACS Chem Biol 11:2195-205
Oakes, Scott A; Papa, Feroz R (2015) The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol 10:173-94
Hetz, Claudio; Chevet, Eric; Oakes, Scott A (2015) Erratum: Proteostasis control by the unfolded protein response. Nat Cell Biol 17:1088
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Guo, W-T; Wang, X-W; Yan, Y-L et al. (2015) Suppression of epithelial-mesenchymal transition and apoptotic pathways by miR-294/302 family synergistically blocks let-7-induced silencing of self-renewal in embryonic stem cells. Cell Death Differ 22:1158-69
Huskey, Noelle E; Guo, Tingxia; Evason, Kimberley J et al. (2015) CDK1 inhibition targets the p53-NOXA-MCL1 axis, selectively kills embryonic stem cells, and prevents teratoma formation. Stem Cell Reports 4:374-89
Hetz, Claudio; Chevet, Eric; Oakes, Scott A (2015) Proteostasis control by the unfolded protein response. Nat Cell Biol 17:829-38

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