# Role of Arginase 1 in Retinal Ischemia Reperfusion Injury

> **NIH NIH R00** · UNIV OF ARKANSAS FOR MED SCIS · 2023 · $43,657

## Abstract

Abstract of the parent grant R00EY029373:
Retinal ischemia is a major cause of vision loss in common retinal disease conditions including
diabetic retinopathy, glaucoma, retinopathy of prematurity, and vein occlusion. This project aims
to define the mechanisms of retinal ischemic injury and identify new therapeutic targets.
We have previously demonstrated the involvement of the arginase enzyme in retinal
neurovascular diseases. Arginase has two isoforms. Building upon the lab's finding that the
mitochondrial isoform, arginase 2 (A2), has a deleterious role in retinal ischemia-reperfusion (IR)
injury, we developed a project focusing on the neurovascular protective role of the cytosolic
isoform arginase 1 (A1). Our recently published papers shows a neuroprotective role of A1
expression in myeloid cells. Arginase competes with nitric oxide synthase (NOS) for their common
substrate L-arginine. Nitric oxide (NO) produced by inducible NOS (iNOS) causes neurovascular
degeneration. We predict that A1 upregulation in myeloid cells limits iNOS-derived nitrative and
oxidative stress and reduces inflammation through its downstream metabolites ornithine and
putrescine. Putrescine is the precursor of polyamines and it is formed from ornithine by ornithine
decarboxylase (ODC, the rate-limiting enzyme in polyamine biosynthesis). These metabolites
have been shown to promote reparative myeloid cells through chromatin modification. In line with
this, our preliminary data show that histone deacetylase (HDAC) 3 is increased in the absence of
A1 in both IR-injured retinas and stimulated macrophages. HDAC3 is essential for macrophage
inflammatory gene transcription and it has been shown to suppress A1 expression. Herein, We
propose a novel suppressive effect of A1 on HDAC3. Our central hypothesis predicts that myeloid
A1 protects against retinal IR injury through ODC-mediated suppression of HDAC3. We will be
using mice with myeloid-specific deletion of A1, ODC and HDAC3, as well as the investigational
drug, BCT-100 (a PEGylated form of arginase 1), together with primary macrophages isolation
and treatment with inhibitors for HDAC3 or arginase downstream enzyme, ODC. Our goal is to
achieve the following objectives: First) Determine the effect of manipulating the arginase pathway
on myeloid cells infiltration / activation in retinal IR injury and the therapeutic potential of BCT-
100. Second) Describe the cross talk between the arginase pathway and HDAC3 and determine
whether A1 in myeloid cells mediates its protective effect through suppression of HDAC3. Third)
Determine the role of myeloid specific deletion of HDAC3 on macrophage inflammatory response
and retinal neurovascular injury.

## Key facts

- **NIH application ID:** 10828178
- **Project number:** 3R00EY029373-04S1
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Abdelrahman Fouda
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $43,657
- **Award type:** 3
- **Project period:** 2019-09-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828178

## Citation

> US National Institutes of Health, RePORTER application 10828178, Role of Arginase 1 in Retinal Ischemia Reperfusion Injury (3R00EY029373-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10828178. Licensed CC0.

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