# Role of H-Ras in retinal cell death in diabetes

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2021 · $365,669

## Abstract

ABSTRACT
Diabetic retinopathy remains a major cause of blindness, and despite cutting edge research in the field, the
molecular mechanism of its pathogenesis remains unclear. Our studies have documented a critical role of
matrix metalloproteinase 9 (MMP-9) in diabetic retinopathy, and have demonstrated that cytosolic MMP-9
activation is an early event, that is followed by its mitochondrial accumulation, mitochondrial dysfunction and
mtDNA damage, initiating a vicious cycle of free radicals. Epigenetic modifications play a critical role in MMP-9
transcription, and in diabetes, MMP-9 promoter DNA undergoes dynamic methylation-hydroxymenthlation and
histone modifications. MMP-9 is also regulated by homocysteine, a thiol-containing non-protein amino acid,
and diabetic patients have elevated plasma homocysteine levels. Increased homocysteine is implicated in
cellular and metabolic abnormalities including mitochondrial damage and epigenetic modifications.
Homocysteine is also a precursor of hydrogen sulfide (H2S), and due to impaired homocysteine metabolism,
plasma levels of H2S are decreased in diabetic patients. Based on these, our central hypothesis is that in
diabetes, high homocysteine activates MMP-9 and disturbs mitochondrial dynamics, and the damaged
mitochondria accelerates apoptosis resulting in the development of diabetic retinopathy.
Aim 1 will investigate the mechanism(s) by which homocysteine activates MMP-9 in diabetes, and the model
predicts that high homocysteine activates MMP-9 by (i) damaging interactions between MMP-9 and its tissue
inhibitor, Timp1, and (ii) inducing epigenetic modifications and increasing the ratio of MMP-9-Timp1. Aim 2 will
determine the mechanism(s) by which homocysteine impairs mitochondrial dynamics, and will test the
hypothesis that homocysteine increases mitochondrial fragmentation, and dysfunctional mitophagy in diabetes
fails to properly remove the fragmented mitochondria. Aim 3 will examine the therapeutic potential of regulating
homocysteine-H2S metabolic balance on inhibition of diabetic retinopathy. The plan will employ in vitro (retinal
endothelial cells) and in vivo (retinal microvessels from rodents) models of diabetic retinopathy, and will utilize
fully optimized molecular biological and pharmacological approaches. Our overall goal is to identify novel
regulatory mechanisms involved in the pathogenesis of diabetic retinopathy, specifically at the level of
regulation of homocysteine-H2S. The proposal is based on a testable central hypothesis, and our proposed
studies are innovative and carry a significant translational impact as they are expected to identify novel
therapeutic targets to prevent the development and progression of diabetic retinopathy. This will offer patients
additional therapeutic means to prevent/halt this sight-threatening complication of diabetes.

## Key facts

- **NIH application ID:** 10133656
- **Project number:** 5R01EY014370-12
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** RENU A. KOWLURU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $365,669
- **Award type:** 5
- **Project period:** 2004-09-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133656

## Citation

> US National Institutes of Health, RePORTER application 10133656, Role of H-Ras in retinal cell death in diabetes (5R01EY014370-12). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10133656. Licensed CC0.

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