# Identifying genetic regulators of hepatic reductive stress in diversity outbred mice

> **NIH NIH R03** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $129,893

## Abstract

NADH is a metabolic cofactor that, along with its oxidized form, NAD+, participates in hundreds of
reduction/oxidation (redox) reactions that power cellular metabolism. A relative increase in NADH levels
promotes reduction and is thought to be a source of metabolic stress (“reductive stress”), though the
precise consequences of reductive stress in vivo have been difficult to study due to a lack of tools with
which to precisely manipulate NADH levels. Using a newly developed tool that enables precise tissue-
specific manipulation of NADH, we recently demonstrated that the metabolite -hydroxybutyrate was a
biomarker of hepatic reductive stress, and that hepatic reductive stress was causally linked to a number
of important metabolic traits. The long-term goal of this work to better understand the genetic
architecture of hepatic reductive stress, and in doing so both expand our understanding of its metabolic
and physiologic consequences and to identify potential genes that might be targeted to alter
metabolism in beneficial ways. Our central hypothesis is that genetic regulators of hepatic reductive
stress can be identified in the diversity outbred (DO) mouse cohort by combining existing genotyping
and RNAseq data with measurements of mouse plasma -hydroxybutyrate levels. The rationale for this
proposal is that, having demonstrated that reductive stress influences many important metabolic traits,
identifying genetic regulators of reductive stress will provide key regulators of this important metabolic
parameter and is significant as this will inspire novel therapeutic targeted paradigms. This work is
innovative in that it leverages new insight that plasma -hydroxybutyrate is biomarker of hepatic NADH
levels to use plasma from a genetically diverse mouse cohort to identify causal genetic influences of this
parameter.

## Key facts

- **NIH application ID:** 10354824
- **Project number:** 1R03DK131243-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Russell Paul Goodman
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $129,893
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10354824

## Citation

> US National Institutes of Health, RePORTER application 10354824, Identifying genetic regulators of hepatic reductive stress in diversity outbred mice (1R03DK131243-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10354824. Licensed CC0.

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