The 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 discovered an unexpected role for the tyrosine kinase c?Abl in the UPR. The studies outlined in this proposal will explore how pharmacological modulation of this multi?domain kinase affects cellular fate under ER stress.

Public Health Relevance

Stress-induced ?-cell dysfunction and death is a signature of type 2 diabetes and autoimmune-driven type 1 diabetes. Drugs that ameliorate stress-induced ?-cell dysfunction hold promise for preventing and controlling type 1 and type 2 diabetes. This project will define a new mechanism of unmitigated ?-cell stress and determine the optimal strategy for pharmacologically modulating this pathway.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK116064-01
Application #
9434929
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Wang, Xujing
Project Start
2018-01-01
Project End
2022-12-31
Budget Start
2018-01-01
Budget End
2019-12-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Washington
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195