# BLR&D Research Career Scientist Award Application

> **NIH VA IK6** · CHARLIE NORWOOD VA MEDICAL CENTER · 2021 · —

## Abstract

Project Summary:
The goal of Dr. Caldwell’s current VA research is to delineate the molecular mechanisms that lead
to trauma-induced retinal neuronal and vascular injury and identify novel strategies to prevent or
reverse the damage and preserve vision. The lack of understanding of the detailed molecular
mechanisms by which ocular trauma damages the retinal neurons and vascular cells represents
a critical knowledge gap in developing effective therapies. Therefore, the goal of this research is
to define these mechanisms and identify innovative approaches to prevent such damage, improve
functional outcomes and reduce the risk of blindness to veterans returning from the battlefield.
Dr. Caldwell’s group has shown that ischemia or trauma-induced activation of the mitochondrial,
ureohydrolase enzyme arginase 2 causes microglia/macrophage activation and neurovascular
degeneration by increasing oxidative stress and inflammation. Overactive arginase can increase
oxidative stress by 1) decreasing the L-arginine supply needed by nitric oxide synthase (NOS) to
produce NO, thereby causing NOS to become uncoupled and produce superoxide that reacts
with NO to form the toxic oxidant peroxynitrite and/or 2) causing excessive activation of the
ornithine-polyamine pathway, thereby leading to polyamine oxidation and production of toxic
oxidants. Thus, overactive arginase 2 could cause neurovascular damage by uncoupling NOS
and/or activating polyamine oxidase. Their studies are developing this concept in two specific
aims. Aim 1 is testing the hypothesis that traumatic retinal injury is mediated by arginase-induced
uncoupling of NOS and/or altered polyamine metabolism. These studies are determining the
effects of arginase knockdown on inflammation, neurovascular degeneration and retinal function
in mouse models of traumatic retinal injury. The studies are examining the protective effects of
arginase deletion on neurovascular damage in relation to NOS function and polyamine
metabolism, expression of polyamine oxidase enzymes and their activity in producing ROS. The
studies are characterizing retinal structure and function by in vivo imaging and
electroretinography, respectively. The results to date indicate that arginase 2 deletion limits
inflammation and mitigates neurovascular damage/dysfunction by normalizing NOS function and
limiting oxidative stress. Aim 2 studies seek to develop a new therapy for prevention and treatment
of traumatic retinal neurovascular injury. These studies are comparing the treatment efficacy and
safety of inhibiting arginase signaling and/or polyamine metabolism in limiting or preventing
inflammation and retinal neurovascular injury in models of traumatic retinal injury as explained for
Aim 1. The outcomes include validation of the arginase/polyamine pathway as a novel target for
therapeutic intervention to attenuate oxidative stress, inflammation and neurovascular
degeneration and promote healthy repair following traumatic retinal injury....

## Key facts

- **NIH application ID:** 10118014
- **Project number:** 5IK6BX005228-02
- **Recipient organization:** CHARLIE NORWOOD VA MEDICAL CENTER
- **Principal Investigator:** Ruth B Caldwell
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-04-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10118014

## Citation

> US National Institutes of Health, RePORTER application 10118014, BLR&D Research Career Scientist Award Application (5IK6BX005228-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10118014. Licensed CC0.

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