Numerous recent studies link development of diabetes to endoplasmic reticulum (ER) stress, a condition that occurs whenever protein-folding requirements overwhelm protein-folding capacity in the secretory pathway. Notably, there is mounting evidence that ER stress contributes to diminished glucose-responsive insulin secretion in ?-cells, to ?-cell apoptosis, and to general peripheral insulin resistance, all hallmarks of type 2 diabetes; additionally ER stress is evident in type 1 diabetes. ER stress triggers the unfolded protein response (UPR) pathway, which slows translation and transcriptionally upregulates genes that enhance ER protein-folding capabilities. If homeostasis is not restored through these outputs, the UPR triggers apoptosis instead. We hypothesize that key components of the UPR, act as toggling switches between homeostatic and apoptotic outputs, ultimately controlling ?-cell fate. Our project goal is to study these switches at the molecular level, using interventional approaches.

Public Health Relevance

Type 2 diabetes mellitus (T2D) affects 18 million Americans, with national healthcare and lost productivity costs exceeding $100 billion per year. T2D begins as a state of compensated insulin resistance; frank disease develops when approximately 50% of insulin-producing pancreatic islet ?-cells of affected individuals undergo cell death. A detaile understanding of how ?-cells die is necessary to rationally mount an assault on all forms of diabetes, including also type 1 diabetes (T1D). We hypothesize that the stress from having to overwork may be generally responsible for ?-cell death in diabetes. In this proposal we are testing this concept using molecular, cellular, and interventional approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK080955-07
Application #
8884590
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Haft, Carol R
Project Start
2008-04-01
Project End
2018-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
7
Fiscal Year
2015
Total Cost
Indirect Cost
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
94118
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
Ghosh, Rajarshi; Wang, Likun; Wang, Eric S et al. (2014) Allosteric inhibition of the IRE1? RNase preserves cell viability and function during endoplasmic reticulum stress. Cell 158:534-48
Maly, Dustin J; Papa, Feroz R (2014) Druggable sensors of the unfolded protein response. Nat Chem Biol 10:892-901
Upton, John-Paul; Wang, Likun; Han, Dan et al. (2012) IRE1ýý cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2. Science 338:818-22
Wang, Likun; Perera, B Gayani K; Hari, Sanjay B et al. (2012) Divergent allosteric control of the IRE1? endoribonuclease using kinase inhibitors. Nat Chem Biol 8:982-9
Lerner, Alana G; Upton, John-Paul; Praveen, P V K et al. (2012) IRE1? induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab 16:250-64
Shore, Gordon C; Papa, Feroz R; Oakes, Scott A (2011) Signaling cell death from the endoplasmic reticulum stress response. Curr Opin Cell Biol 23:143-9
Merksamer, Philip I; Papa, Feroz R (2010) The UPR and cell fate at a glance. J Cell Sci 123:1003-6
Han, Dan; Lerner, Alana G; Vande Walle, Lieselotte et al. (2009) IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 138:562-75