Numerous recent studies link development of type 2 diabetes (T2D) 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 generalperipheral insulin resistance, all hallmarks of T2D. ER stress triggers the unfolded protein response (UPR) pathway, which slows translation and transcriptionallyupregulates genes that enhance ER protein-folding capabilities. If homeostasis is not restored through these outputs, the UPR triggers apoptosis instead. We hypothesize that key component of the UPR, act as a 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 ?-cellsof affected individuals undergo cell death. A detailed understanding of how ?-cells die is necessary to rationally mount an assault on T2D. We hypothesize that the stress from having to overwork may be responsible for ?-cell death in T2D. In this proposal we are testing this concept using molecular and cellular approaches.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK080955-05
Application #
8478087
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Haft, Carol R
Project Start
2009-07-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$317,823
Indirect Cost
$112,112
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
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
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