# Itaconate and Immunometabolism in Ischemic Stroke

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $37,270

## Abstract

Project Summary/Abstract:
 Stroke is the fifth leading cause of mortality in the United States and the leading cause of permanent
disability in older adults. Thrombolytic therapy that causes reperfusion is the only FDA approved therapy for
patients that have suffered an occlusive stroke. However, this treatment is only used in 5% of reported cases.
Myeloid cell modification leading to modulation of the inflammatory response is a potential treatment in stroke,
but to date has not successfully been translated into a viable treatment. Previous research has shown that
myeloid cell modification to an anti-inflammatory phenotype is protective in cerebral ischemia/reperfusion (I/R).
Immune cell metabolism has recently been shown to be a major factor involved in immune cell modulation.
Itaconate, the metabolic intermediate that is produced by the enzyme aconitate decarboxylase (ACOD1) from
the TCA cycle intermediate aconitate, has been shown to be protective in a cardiac model of
ischemia/reperfusion by using dimethyl itaconate (DMI) a cell-permeable form. DMI has shown to exert anti-
inflammatory effects on macrophages, and to decrease reactive oxygen species (ROS) formation in vitro.
However, the role of the endogenous itaconate production by ACOD1 has not been addressed. Our
preliminary data shows that germline ACOD1 deletion leads to increased ischemia/reperfusion induced infarct
size following transient MCA occlusion (tMCAo). We confirm that DMI and 4-octyl itaconate (4-OI) decrease
inflammatory genes in vitro. We propose to test the role of ACOD1 in stroke and determine what cell types are
important by using ACOD1 floxed animals and myeloid, microglial and astrocyte specific knockout. We will also
test whether DMI or 4-OI can be protective in stroke. We will quantify infarct size in wild type or ACOD1 cell-
specific knockout mice with and without treatment of DMI or 4-OI in tMCAo to determine effects in this model.
The production of itaconate has been shown to contribute to alteration of metabolism with decreases in
oxidative phosphorylation, the buildup of intracellular succinate and increase in glycolysis. We propose to use
metabolomics analysis to measure intracellular metabolite intermediates such as succinate, metabolic flux and
reactive oxygen species. Upon completion of this fellowship project, these studies will allow for better
understanding of the mechanism behind itaconates protective effects on ischemia/reperfusion injury and give
better insight into possible treatments for patients that suffer from ischemic stroke.

## Key facts

- **NIH application ID:** 9999292
- **Project number:** 5F31NS108617-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Thomas M Vigil
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,270
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999292

## Citation

> US National Institutes of Health, RePORTER application 9999292, Itaconate and Immunometabolism in Ischemic Stroke (5F31NS108617-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9999292. Licensed CC0.

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