# Genetic Map of the Mammalian Cell Response to Environmental Stress

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2024 · $440,000

## Abstract

A wide variety of environmental stressors, from pesticides to common anticancer chemotherapies, result in
protein damage. This damage underlies diseases such as cancer and neurodegeneration, and when caused by
prescription drugs, leads to toxic side effects limiting usage. To cope with these proteotoxic stresses, cells
express molecular chaperones, co-chaperones, and a variety of additional support proteins – collectively referred
to as the proteostasis network (PN) – that are integral for the proper synthesis, folding, stability and degradation
of the cellular proteome. Thus, understanding the regulation and function of the PN is critically important in
understanding its role in the interface between disease susceptibility and exposure to environmental stressors.
We previously developed a broadly applicable framework and online resource (FIREWORKS) to interrogate
biological networks using unbiased genetic screens. Using our FIREWORKS framework, we mapped the
constituents of and relationships between stress response pathways in human cells coping with growth-related
molecular stresses revealing a network of 146 genes with vital functions spanning diverse stress contexts. Here,
we propose to expand this resource to create an unbiased and global map of the response to environmental
proteotoxic stress. We will integrate our cutting-edge chemical-genetic screening platform with our FIREWORKS
computational pipeline to identify components, function, and regulatory nodes critical for the cellular response to
environmental stressors. In parallel, we will identify transcriptional changes that occur immediately and
throughout longer periods of environmental stress exposure, to provide a framework for understanding cellular
adaptation to these stressors. Collectively, this map will serve as a major resource for the research community,
provide a more complete understanding of cellular environmental stress response programs, and lead to insights
into the large variability in the risk of adverse events that arise from exposure to these insults.

## Key facts

- **NIH application ID:** 10791616
- **Project number:** 1R21ES035975-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Marc Mendillo
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $440,000
- **Award type:** 1
- **Project period:** 2024-09-05 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10791616

## Citation

> US National Institutes of Health, RePORTER application 10791616, Genetic Map of the Mammalian Cell Response to Environmental Stress (1R21ES035975-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10791616. Licensed CC0.

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