# Regulation of O-GlcNAcylation During Injury

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $409,375

## Abstract

Summary
 The modification of intracellular proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) has emerged as a
novel regulator of cytoprotection. Numerous forms of cellular injury, including cardiac ischemic preconditioning
(acute, prolonged, and remote), lead to elevated levels of O-GlcNAc in both in vivo and in vitro models. Elevating
O-GlcNAcylation before, or immediately after, the induction of cellular injury is protective in models of ischemia
reperfusion (I/R) injury, as well as heat stress, oxidative stress, endoplasmic reticulum stress, hypoxia, and
trauma hemorrhage. Together, these data suggest that O-GlcNAc is a novel endogenous cardioprotective
agent. To date, the majority of work studying the O-GlcNAc modification in models of I/R injury has focused on
identifying the proteins and mechanisms by which O-GlcNAc mediates cardioprotection. However,
understanding the regulation of the O-GlcNAc modification during injury is critical and is yet unstudied. The goal
of this proposal is to map the regulatory networks of the enzymes that cycle the O-GlcNAc modification, the O-
GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Specifically, we will complete the following aims:
Aim 1. Define the impact of protein-protein interactions on OGT and OGA activity and substrate targeting
 in the injured heart. Quantitative mass spectrometry will be used to identify protein-interactors of OGT
 and OGA. A combination of biochemical approaches will be used to interrogate the role of these effector-
 proteins on O-GlcNAc cycling in the ischemic heart.
Aim 2. Map the OGT and OGA covalent-regulatory networks in the injured heart. The O-GlcNAc
 modification sites, and other covalent-regulators, of OGT and OGA will be identified. The impact of O-
 GlcNAcylation on OGT/OGA function will be assessed in models of oxidative stress and I/R injury.
 Collectively, we anticipate that these studies will define the pathways that regulate OGT, OGA, and O-
GlcNAcylation during I/R injury. This critical insight will provide a framework for investigating novel therapeutic
targets for myocardial infarction and an understanding about how the O-GlcNAc-mediated stress response is
dysregulated contributing to cardiovascular disease

## Key facts

- **NIH application ID:** 9979937
- **Project number:** 5R01HL139640-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Natasha Elizabeth Zachara
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $409,375
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979937

## Citation

> US National Institutes of Health, RePORTER application 9979937, Regulation of O-GlcNAcylation During Injury (5R01HL139640-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9979937. Licensed CC0.

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