# Delineating the role of TIMP3 in macular degeneration

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2024 · $490,475

## Abstract

ABSTRACT
The retinal pigment epithelium-choriocapillaris (RPE-CC) complex is the primary site of disease pathogenesis in
several eye diseases, including age-related macular degeneration (AMD) and related macular dystrophies, like
Sorsby’s fundus dystrophy (SFD). Notably, sub-RPE accumulation of tissue inhibitor of metalloproteinase 3
(TIMP3) is a prominent feature of SFD/AMD. However, it is not known “how” sub-RPE TIMP3 accumulation
promotes SFD/AMD pathology. This is partially because the RPE-CC is a functional composite making it difficult
to study the contribution of spatial changes in RPE versus CC layer during disease development in vivo.
Furthermore, the lack of a representative model of the RPE-CC in vitro has significantly impacted our ability to
study RPE-CC interaction in vitro. Using induced pluripotent stem cells (iPSCs), we have developed an iPSC-
RPE-CC model that recapitulate key features of both healthy and AMD/SFD eyes. Specifically, iPSC-RPE-CC
shows evidence of fenestrated CC-like vasculature and Bruch’s membrane like ECM. Similarly, SFD iPSC-RPE-
CC displays two central hallmarks of SFD/AMD, drusen and choroidal neovascularization (CNV)-like pathology.
Notably, longitudinal analyses of control versus SFD iPSC-model showed that sub-RPE TIMP3 accumulation
occurs relatively early and precedes maculopathy cellular events. Furthermore, our preliminary proof of concept
studies shows that sub-RPE TIMP3 accumulation in the SFD iPSC model promotes pro-maculopathy cellular
changes via dysregulated lipid metabolism and sterile inflammation. Based on these strong preliminary studies,
the overall goal of this proposal is to establish the independent contribution of sub-RPE TIMP3 accumulation to
AMD/SFD pathology development. We will perform spatial (RPE versus CC) and temporal (e.g., prior and after
drusen formation) manipulation of TIMP3 expression/activity in i) SFD iPSC-RPE-CC and ii) control iPSC-RPE-
CC cultures (iPSCs derived from healthy subjects with normal vision) to test the hypotheses that sub-RPE TIMP3
accumulation leads to dysregulated lipid metabolism and sterile inflammation and consequently i) drusen
beneath the RPE monolayer and ii) CC atrophy and CNV. From a therapeutic standpoint, we will
pharmacologically target dysregulated lipid metabolism and sterile inflammation in SFD/AMD iPSC models.

## Key facts

- **NIH application ID:** 10879073
- **Project number:** 5R01EY028167-08
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Ruchira Singh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $490,475
- **Award type:** 5
- **Project period:** 2017-09-30 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879073

## Citation

> US National Institutes of Health, RePORTER application 10879073, Delineating the role of TIMP3 in macular degeneration (5R01EY028167-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10879073. Licensed CC0.

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