Structural maturation and folding of secretory and transmembrane proteins begins in the endoplasmic reticulum (ER). These processes are catalyzed by an ER-resident protein-folding machinery comprising molecular chaperones, oxidoreductases, and other protein-modifying enzymes. If demand on the secretory pathway exceeds capacity, these ER-resident activities become overwhelmed, leading client proteins to accumulate in unfolded forms. During such instances of 'ER stress,'affected cells are at increased risk for degeneration and death. Accruing evidence implicates endoplasmic reticulum (ER) stress in the etiology and pathogenesis of diabetes mellitus (both types 1 and 2) in humans. The unfolded protein response (UPR), a collection of signaling pathways that attempt to correct ER stress, has been defined and extensively studied. Under ER stress, the UPR sets in motion transcriptional and translational changes that promote adaptation. However, irremediable levels of ER stress cause these adaptive measures to end, and instead usher in a terminal UPR that drives cells toward dysfunctional and diseased states, often leading to programmed cell death. We have identified the master UPR regulator-IRE1?-as a key gatekeeper of the terminal UPR. IRE1? is a bifunctional kinase/endoribonuclease (RNase) that has divergent outputs that determine cell fate. The overall goal of this project is to advance novel kinase inhibitors for early-stage pharmacological validation of this key target controlling entry of cells into the terminal UPR, and to thereby develop pre-therapeutic lead compounds for disease modification in human diabetes mellitus.

Public Health Relevance

This project will pharmacologically validate a key gatekeeper of the terminal UPR as a drug target for the treatment of diabetes. These efforts have the potential to provide valuable starting points for the treatment of diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK100623-01
Application #
8614223
Study Section
Special Emphasis Panel (ZRG1-EMNR-R (56))
Program Officer
Haft, Carol R
Project Start
2014-01-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$501,998
Indirect Cost
$118,325
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