# Cellular Mechanisms of Retinopathy: Role of Arginase

> **NIH NIH R01** · AUGUSTA UNIVERSITY · 2021 · $373,450

## Abstract

PROJECT SUMMARY
This proposal addresses a problem of great clinical significance: the lack of effective therapies to limit
neurovascular injury and promote repair during the early stages of potentially blinding ischemic retinopathies.
We propose studies designed to show that increasing activity of the arginase 1 enzyme in immune cells offers
a novel and highly effective strategy for limiting neurovascular injury and promoting retinal tissue repair in the
early stages of ischemic retinopathy. Our previous studies have shown that the urea hydrolase enzyme
arginase is critically involved in neurovascular injury in diabetic retinopathy (DR), ischemia/reperfusion injury
(IR) and oxygen-induced retinopathy (OIR). Arginase metabolizes L-arginine to form polyamines, proline, and
glutamate. Catabolic products of polyamine oxidation and glutamate can promote oxidative injury and cell
death. Excessive arginase activity also can reduce the supply of L-arginine substrate needed for production of
nitric oxide (NO) by NO synthase (NOS). Our studies in models of DR have shown that increased
expression/activity of the arginase 1 (A1) isoform is involved in vascular dysfunction and premature
senescence by a mechanism involving decreased NO formation by endothelial NOS (eNOS). In contrast, our
studies in models of IR and OIR indicate that the arginase 2 (A2) isoform is involved in neurovascular injury by
mechanisms involving upregulation of inducible NOS (iNOS) and tumor necrosis factor-α (TNFα) which leads
to cell death via activation of the TNF receptor interacting protein 3 kinase (RIP3)/dynamin-related protein 1
(DRP1) axis. Preliminary data also show that deletion of A2 limits this damage by a mechanism involving
increased A1 expression and suppressed iNOS-mediated NO formation. A1 deletion globally or in myeloid-
derived cells, or MΦ depletion aggravates the injury whereas intravitreal injection of Pegylated recombinant A1
(PegA1) limits damage. Based on our prior work and preliminary data, we hypothesize that A1 protects against
retinal ischemic neurovascular injury by reducing iNOS levels and promoting MΦ/myeloid cell-mediated pro-
survival function. This will be tested by the following aims: Aim 1 will determine the role of A1 expression in IR-
induced neurovascular injury. Aim 2 will determine whether A1 limits IR-induced injury by promoting reparative
MΦ. Aim 3 will determine the role of A1 in OIR-induced neurovascular injury and test its potential in therapeutic
repair. If successful, the proposed studies will represent a paradigm shift in the field of retinopathy research by
identifying A1 as a mediator of neuroprotection and vascular repair.

## Key facts

- **NIH application ID:** 10219253
- **Project number:** 5R01EY011766-22
- **Recipient organization:** AUGUSTA UNIVERSITY
- **Principal Investigator:** ROBERT William CALDWELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $373,450
- **Award type:** 5
- **Project period:** 1998-03-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219253

## Citation

> US National Institutes of Health, RePORTER application 10219253, Cellular Mechanisms of Retinopathy: Role of Arginase (5R01EY011766-22). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10219253. Licensed CC0.

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