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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01DK080955-06
Application #
8695105
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Haft, Carol R
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Maly, Dustin J; Papa, Feroz R (2014) Druggable sensors of the unfolded protein response. Nat Chem Biol 10:892-901
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