# Defining the genetic architecture of multi-stress response

> **NIH NIH R35** · UNIVERSITY OF ARIZONA · 2020 · $377,482

## Abstract

ABSTRACT
The goal of the work outlined in this proposal is to understand the fundamental biology of cellular response to
different forms and combinations of stress. 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 types of intervention improve resistance
to multiple forms of stress (e.g. dietary restriction, inhibition of insulin signaling), surprisingly little is known
about how these responses differ when cells are challenged with multiple types of stress simultaneously. The
molecular architecture underlying multi-stress response represents a critical knowledge gap in the field. This
gap 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
network of molecular pathways that underlie stress response, we aim to identify specific intervention points that
can be targeted to target different stress profiles. Our lab employs a novel platform for high-throughput health
and survival analysis in Caenorhabditis elegans. Combining this platform with tools in systems and classical
genetics, we will: (1) define the genetic network that modulates the response to multiple forms of stress in C.
elegans; (2) determine which network components are activated in response to distinct combinations of stress;
(3) investigate mechanisms of cross-adaptation—mild exposure to one stress imparting resistance to another
form of stress—for different combinations of stressors; and (4) identify key intervention points that can be
targeted to mitigate different combinations of cellular stress. Using this approach, we have identified 3-
hydroxyanthranilic acid (3HAA), a metabolite in the tryptophan-kynurenine pathway, that improves survival and
health in C. elegans by mitigating both oxidative stress and ER stress. These benefits are realized, at least in
part, through direct antioxidant and chaperone activity by 3HAA. We are now beginning mouse studies to
validate our mechanistic model for the action of 3HAA in a mammalian system. The long-term goal of our work
is to answer several outstanding questions about the fundamental biology of cellular stress response: (1) How
is the genetic network underlying cellular stress response organized? (2) Which elements of this stress
response network are general (i.e. responsive to a wide range of types of stress) and which are specific (e.g.
responsive to only specific stressors)...

## Key facts

- **NIH application ID:** 9984485
- **Project number:** 5R35GM133588-02
- **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:** $377,482
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984485

## Citation

> US National Institutes of Health, RePORTER application 9984485, Defining the genetic architecture of multi-stress response (5R35GM133588-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9984485. Licensed CC0.

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