# Altered RPE matrix in Sorsby Fundus Dystrophy leads to metabolic dysfunction

> **NIH NIH F31** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $38,663

## Abstract

Project Summary/Abstract
Age-related macular degeneration (AMD), is the leading cause of blindness in adults over 50 with no effective
treatments available. AMD is caused by multiple genetic and environmental factors making it difficult to replicate
and study in the laboratory. In contrast, Sorby’s Fundus Dystrophy (SFD) is a rare monogenetic disease caused
by mutations in Tissue inhibitor of metalloproteinase 3 (TIMP3) that has significant phenotypic similarities to
AMD. Using animal and cell culture models of SFD, I hope to understand the underlying pathogenic and
molecular mechanisms of RPE/retinal degeneration in SFD and possibly AMD. The retina has a uniquely high
metabolic demand and all nutrients needed to power the retina must be transported across or generated by RPE.
Furthermore, proper RPE metabolism is required for the retina to receive adequate nutrients. Retina utilize
aerobic glycolysis to generate ATP and therefore primarily utilize glucose as their energy substrate. Based on
preliminary data from the Anand-Apte laboratory, I hypothesize that aberrant energy metabolism in the RPE
results in nutrient deprivation in the retina and is a significant contributor to SFD pathology. To address this
hypothesis, I propose 2 specific aims; (i) to determine if SFD RPE cells are deficient in their ability to
produce and/or transport essential metabolites to the retina. Using metabolomics and stable isotopic tracing
within SFD mouse and human ARPE19 cell culture models. I will use gas chromatography mass spectrometry
(GC/MS) to quantify nutrient transport across RPE in vivo and in vitro. The link between TIMP3 mutations and
metabolism perturbations are unclear especially considering that TIMP3 has extracellular localization while
metabolism is an intracellular process. (ii) to investigate if extracellular matrix changes and HA
overproduction are responsible for altered energy metabolism in SFD RPE. Recently, the Anand-Apte
laboratory has reported that SFD RPE expressing mutant TIMP3 S179C produce excess hyaluronan (HA), a
glucosamine that is highly abundant in the extracellular matrix (ECM). I hypothesize that HA overproduction in
SFD RPE cells is responsible for the metabolic phenotype we have observed. Since HA is synthesized from
glycolytic intermediates, HA could impact energy metabolism through multiple mechanisms. Understanding the
details of macular degeneration is the first step towards discovering effective prophylactics and will aid in the
development of new therapeutics.

## Key facts

- **NIH application ID:** 10315337
- **Project number:** 1F31EY033223-01
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** ALLISON Brooke GRENELL
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $38,663
- **Award type:** 1
- **Project period:** 2021-09-10 → 2023-09-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10315337

## Citation

> US National Institutes of Health, RePORTER application 10315337, Altered RPE matrix in Sorsby Fundus Dystrophy leads to metabolic dysfunction (1F31EY033223-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10315337. Licensed CC0.

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