# Defining the genetic architecture of multi-stress response

> **NIH NIH R35** · UNIVERSITY OF ARIZONA · 2020 · $219,779

## Abstract

ABSTRACT
Cells are constantly subjected to a variety of intrinsic and extrinsic stresses—oxidative, protein misfolding,
osmotic—that have deleterious impact on cellular structures and function. In response, eukaryotic cells activate
a range of molecular pathways to mitigate and repair damage—oxidative stress response, unfolded protein
response, osmotic stress response. While substantial molecular detail is known about individual stress
response pathways, and some interventions improve resistance to multiple forms of stress (e.g. dietary
restriction), surprisingly little is known about how cells respond differently when challenged with multiple types
of stress simultaneously. The molecular architecture underlying multi-stress response is a critical knowledge
gap with has broad implications for medicine. Human diseases rarely involve a single form of stress—
Alzheimer’s disease is characterized by neuroinflammation, increased oxidative stress, and accumulation of
misfolded proteins, while cancer exhibits oxidative stress, DNA damage, and localized hypoxia. By
understanding the molecular network underlying stress response, we aim to identify specific intervention points
to target distinct stress profiles. Our lab employs a novel platform for high-throughput health and survival
analysis in Caenorhabditis elegans. Combining this platform with analytical tools in genetics and molecular
tools for stress response (e.g. fluorescence stress response reporters), we will: (1) define the genetic network
that modulates multi-stress response; (2) determine which components are activated in response to distinct
stress combinations; (3) investigate mechanisms of cross-adaptation—mild exposure to one stress imparting
resistance other forms of stress; and (4) identify key intervention targets to mitigate different stress
combinations. Selected stress combinations, modes of cellular response, and interventions will be validated in
human cell culture and mouse models. Our long-term goal is to answer key questions in the biology of stress
response: How is the genetic stress response network organized? Which elements general and which are
specific to distinct stress types? How does response to stress alter an organism’s resistance other types?
What nodes in the stress response network that can be targeted to improve health or treat specific diseases?
Here we propose to purchase a new confocal microscopy system as an Administrative Supplement to support
this work.

## Key facts

- **NIH application ID:** 10134552
- **Project number:** 3R35GM133588-02S1
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** George Lewis Sutphin
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $219,779
- **Award type:** 3
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134552

## Citation

> US National Institutes of Health, RePORTER application 10134552, Defining the genetic architecture of multi-stress response (3R35GM133588-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10134552. Licensed CC0.

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