# Homocysteine's role in Age-Related Macular Degeneration

> **NIH NIH R01** · OAKLAND UNIVERSITY · 2022 · $360,490

## Abstract

Summary/Abstract
Age-related macular degeneration (AMD) is the leading cause of vision loss in among elderly populations.
Elevated homocysteine (Hcy), also known as hyperhomocysteinemia (HHcy) has been reported in patients with
AMD; thereby suggesting an association between HHcy and the risk of AMD. Recently, we reported retinal
changes similar to AMD in a mouse model of HHcy which lacks Cystathionine-β-synthase (cbs+/-) or received
intravitreal injections of Hcy. These models showed significant retinal pigment epithelium (RPE) dysfunction and
choroidal neovascularization (CNV) However, the lack of understanding the molecular/cellular mechanisms of
these changes is a critical barrier in proposing Hcy as a therapeutic target in AMD. Our preliminary data show
that HHcy-induced RPE dysfunction is associated with the upregulation of the N-methyl-D-aspartate (NMDAr)
and GLUT1 receptors and increased glycolysis. Hence, we hypothesize that HHcy contributes to the
pathogenesis of AMD via activation of the NMDAr and GLUT1 signaling pathways that induce the metabolic
switch from oxidative phosphorylation to glycolysis. Therefore, elimination of excess Hcy through
pharmacological or genetic intervention could be beneficial in the treatment of AMD. To test our hypothesis, we
will conduct in vitro experiments, using RPE and choroidal endothelial cells (CEC) and in vivo using cbs+/-, wild
type mice receiving intravitreal injection of Hcy and mice lacking the endothelial or RPE NMDAr (NMDAr-/-E or
NMDAr-/-R respectively). Our specific aims include: 1: Testing the hypothesis that HHcy induces the
metabolic switch from mitochondrial respiration to glycolysis via activation of GLUT1 in RPE cells: We
will examine the changes in the retinal expression and localization of GLUT1, mitochondrial respiration,
glycolysis and rate-limiting glycolytic enzymes in HHcy models. Moreover, we will determine the effect of GLUT1
inhibition on HHcy-induced RPE dysfunction and CNV. Aim 2: Testing the hypothesis that inhibition of
NMDAr preserves RPE function and reduces the development of CNV under HHcy. We will examine the
effects of pharmacological inhibition or genetic manipulation of the NMDAr on HHcy-induced RPE dysfunction
and CNV. The effect of intravitreal injection of Hcy will be evaluated in NMDAr-/-E or NMDAr-/-R as compared to
wild type and cbs+/- mice with or without NAMDAr inhibitors. Parallel in vitro experiments will be performed on
RPE and CEC subjected to Hcy with or without NMDAr inhibitors followed by assessment of RPE function and
angiogenic potential of CEC. Aim 3: Testing the hypothesis that elimination of excess Hcy by dietary
supplementation or genetic/ pharmacological modifications prevents the progression of AMD. Hcy
clearance will be enhanced in models of HHcy through two approaches, followed by assessment of RPE function
and angiogenic potential of CEC: (a) Enhancing the remethylation pathway of Hcy metabolism using vitamins
B6, B12 and folic acid supple...

## Key facts

- **NIH application ID:** 10329922
- **Project number:** 5R01EY029751-05
- **Recipient organization:** OAKLAND UNIVERSITY
- **Principal Investigator:** Amany M Tawfik
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $360,490
- **Award type:** 5
- **Project period:** 2021-08-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10329922

## Citation

> US National Institutes of Health, RePORTER application 10329922, Homocysteine's role in Age-Related Macular Degeneration (5R01EY029751-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10329922. Licensed CC0.

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