# Delineating the role of TIMP3 in macular degeneration

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $385,675

## Abstract

ABSTRACT
Retinal pigment epithelium (RPE) cells in the retina are the major site of disease pathogenesis in numerous
macular degenerative diseases. In a subset of these maculopathies, the primary pathological manifestations
are localized to the RPE-extracellular matrix (RPE-ECM) complex, suggesting that ECM abnormalities
contribute to the underlying disease mechanisms and RPE dysfunction in these maculopathies. In fact,
mutations in TIMP3, a gene involved in ECM regulation, leads to Sorsby's fundus dystrophy (SFD), an
inherited maculopathy with phenotypic alterations that mimic age-related macular degeneration (AMD). In
addition, rare variants of TIMP3 are strongly linked to AMD development and TIMP3 accumulates underneath
the RPE in both SFD and AMD. Together, these findings suggest that TIMP3 biology plays a central role in
maintaining RPE-ECM homeostasis and that TIMP3 dysfunction contributes to pathophysiology of some
maculopathies. However, the consequence of TIMP3 dysfunction on RPE physiology and its role in the
development of macular degeneration has not been established. In this proposal, we will elucidate the
molecular and pathological consequences of TIMP3 mutation in RPE cells using a patient-derived human-
induced pluripotent stem cell (hiPSC)-RPE model of SFD. In preliminary studies, SFD hiPSC-RPE develops
key pathological manifestation of the disease including, drusen formation and accumulation of TIMP3 in the
extracellular matrix. Furthermore, consistent with TIMP3's biological function and pathophysiology of
maculopathies affecting RPE-ECM integrity, SFD hiPSC-RPE displays altered expression of 1) pro-angiogenic
TIMP3-target matrix metalloproteinases (MMPs; MMP2, MMP14), 2) TNF converting enzyme (TACE) and 3)
complement pathway genes. These results support the hypothesis that TIMP3 dysfunction in SFD leads to
dysregulation of ECM-turnover and activation of pro-angiogenic and pro-inflammatory signaling that
consequently leads to drusen formation and RPE-mediated CNV. To test this hypothesis, we will assess the
following predictions in our model system 1)) increased TIMP3 accumulation in ECM in SFD alters ECM
composition/turnover and instigates complement activation in turn promoting drusen formation, 2) TIMP3
dysfunction leads to increased expression/activity of MMPs, MMP2 and MMP14, and thereby impaired barrier
integrity and VEGF release by RPE cells in SFD and 3) TIMP3 dysfunction leads to TNF-induced pro-
inflammatory signaling by RPE. These proposed experiments will provide clear answers the specific role of
TIMP3 mutation/dysfunction in drusen biogenesis and RPE-mediated CNV. Ultimately, the knowledge gained
in this study will help identify potential drug therapies for targeting TIMP3-induced RPE-ECM alterations in SFD
and other maculopathies.!

## Key facts

- **NIH application ID:** 9954085
- **Project number:** 5R01EY028167-04
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Ruchira Singh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,675
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9954085

## Citation

> US National Institutes of Health, RePORTER application 9954085, Delineating the role of TIMP3 in macular degeneration (5R01EY028167-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9954085. Licensed CC0.

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