# Defining the Genetic Architecture of the Glutathione Redox System

> **NIH NIH R01** · UNIVERSITY OF GEORGIA · 2020 · $258,853

## Abstract

PROJECT SUMMARY/ABSTRACT
The endogenous antioxidant glutathione (GSH) confers cells with the ability to resist stress, maintain survival,
and properly regulate fundamental signaling pathways. The levels of GSH within a tissue, as well as the
proportion of its reduced and oxidized forms, appear to be innate, demonstrating that eukaryotes inherit the
relative capacity to synthesize and metabolize GSH. Despite this apparent genetic effect, the genetic
regulation of the GSH system remains poorly defined. Instead, knowledge is currently limited to a small
number of canonical GSH genes such as glutathione reductase (Gr) and glutathione peroxidase-1 (Gpx-1).
Our preliminary studies revealed that the genetic regulation of this system is actually more complex and may
involve a novel set of genes. Those preliminary efforts were based on in silico methods that are at times limited
in power, so it is now paramount to perform high precision gene mapping to validate our newly discovered loci,
and to identify previously overlooked loci. In the current project, we will accomplish those crucial tasks by
testing our central hypothesis: that the GSH system is regulated by genetic variation within i) canonical GSH
genes, including Gr and Gpx-1, and ii) novel genes, such as the RAR-related orphan receptor α (Rorα), whose
functions are external to the basic GSH system, and whose number we expect to exceed that of canonical
GSH genes. We will test the hypothesis with a strategy that couples a forward genetics approach with the
innovative Diversity Outbred (DO) mouse stock, which models the genetic diversity found in humans, and a
reverse genetics approach based on novel mouse models created with CRISPR/Cas9 technology. We will
address the following specific aims: 1) to quantify the heritability of core GSH phenotypes in a genetically
diverse population; 2) to define genomic regions associated with the GSH system, and delineate shared and
tissue-specific loci; and 3) to prioritize candidate genes, and initiate functional analyses of the most compelling
candidates. These studies will define the fundamental genetic architecture of an indispensable biochemical
system that governs cellular stress resistance and survival. Knowledge gained from these efforts will inform a
series of future clinical and mechanistic studies aimed at understanding the impact of GSH genes on cellular
damage during stress, and the data will build a foundation for innovative therapies to maintain tissue integrity in
patients with degenerative diseases, thereby increasing their health spans and improving their qualities of life.

## Key facts

- **NIH application ID:** 9978898
- **Project number:** 5R01GM121551-04
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** Robert Pazdro
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $258,853
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978898

## Citation

> US National Institutes of Health, RePORTER application 9978898, Defining the Genetic Architecture of the Glutathione Redox System (5R01GM121551-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9978898. Licensed CC0.

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