# Investigating the impact of genetic variation on ER stress response and disease

> **NIH NIH R35** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $381,250

## Abstract

PROJECT SUMMARY
One of the biggest challenges to treating disease is the fact that individuals carrying the same
pathogenic mutation can present with different disease outcomes. It is increasingly recognized
that this variation can arise, in large part, due to genetic background differences of each individual.
In some cases, this genetic variation appears to be more important than the underlying causative
mutation. In order to truly understand how genetic variation interacts with disease causing
mutations, laboratory disease studies need to take into account genetic variation. We are applying
this approach to the endoplasmic reticulum (ER) stress response. The ER is a large organelle
responsible for the synthesis, maturation, and delivery of proteins responsible for a variety of
essential functions. ER stress occurs when misfolded proteins accumulate in the lumen of the
ER. If left unresolved, cell death occurs, followed by disease. The cell responds to ER stress with
the unfolded protein response (UPR). The UPR initiates a very large transcriptional response that
is aimed at clearing misfolded proteins from the ER. ER stress is an important component to a
number of common and rare diseases, including diabetes and neurodegenerative disorders.
Importantly, many studies are now showing that pharmacological or genetic modification of the
ER stress response can alter the outcome of many diseases. We hypothesize that genetic
variation in the ER stress response is an important contributor to variability in disease. In order to
test this, we need to understand the nature and mechanism by which ER stress varies among
individuals. We utilize a number of tools in mouse and Drosophila to understand the role of genetic
variation. We have recently demonstrated that the ER stress response and outcomes of disease
of the ER stress response are incredibly variable and complex across individuals and genetic
backgrounds. Our long term goal is to understand how genes and genetic variants interact to
produce such a variable response. To do this, we will focus on two areas in this proposal: 1)
Uncover the genetic architecture underlying genetic variation of the ER stress response in the
mouse. We propose a number of studies aimed at understanding this at the genome-wide level,
gene level, and SNP level; and 2) understand how genetic modifiers influence the phenotypic
outcome of diseases of the ER stress response. Knowing how genetic variation impacts a critical
disease-relevant pathway, like ER stress, will assist in designing personalized therapies that
might better treat the individual patient.

## Key facts

- **NIH application ID:** 10229453
- **Project number:** 5R35GM124780-05
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Clement Chow
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10229453

## Citation

> US National Institutes of Health, RePORTER application 10229453, Investigating the impact of genetic variation on ER stress response and disease (5R35GM124780-05). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10229453. Licensed CC0.

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