# Interrogation of the Roles of Tyrosine Kinases in the Unfolded Protein Response

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $525,712

## Abstract

Abstract
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.

## Key facts

- **NIH application ID:** 10072089
- **Project number:** 5R01DK116064-04
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Dustin J Maly
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $525,712
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072089

## Citation

> US National Institutes of Health, RePORTER application 10072089, Interrogation of the Roles of Tyrosine Kinases in the Unfolded Protein Response (5R01DK116064-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10072089. Licensed CC0.

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