# Nuclear receptor driven mechanisms in aging and AMD

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $432,544

## Abstract

Summary
Dry age-related macular degeneration (AMD) is the leading cause of vision loss in the Western World with a
complex etiology. The fundamental abnormalities occurring in retinal pigment epithelial (RPE) cells, resulting in
their progressive dysfunction and subsequent atrophy in AMD, are still not known. However, candidate
pathogenic pathways linked to development of disease have emerged from the convergence of a sundry of
epidemiological, genetic, morphological, and biochemical studies, including inflammation, lipid dysregulation,
apoptosis, and RPE barrier dysfunction among others. Currently there are no drugs available to treat dry AMD.
However, targeting a potential master regulator of these pathways is one avenue to pursue.
Our overarching goal is to discover molecular mechanisms by which nuclear receptors modulate pathologies
characteristic of AMD. In this proposal we concentrate on investigating the biology and function of NURR1
(NR4A1, Nuclear Receptor Related-1 protein), an orphan nuclear receptor, in cells vulnerable in AMD. Studies
of the central nervous system as well as some systemic diseases have revealed NURR1 as a regulator of a
variety of biological processes including cellular proliferation, differentiation, apoptosis, inflammation, lipid
homeostasis and metabolism, highlighting its importance in overall cell health. However, as a nuclear receptor,
its role has also been shown to vary and be ligand and cell/tissue specific. Given the overlap between process
regulated by NURR1 and those important in the development and progression of AMD, we propose to
systematically investigate NURR1’s role and potential for therapeutic targeting in ocular cells including RPE, as
this has yet to be discovered.
Herein we build on preliminary observations including (1) NURR1 expression in human RPE cells decreases
with age; (2) NURR1 accumulates extracellularly in drusen and basal deposits of human AMD donor tissue; (3)
NURR1 activation attenuates TNFa-induced RPE epithelial-to-mesenchymal (EMT) transition in vitro; and (4)
oral administration of a NURR1 activating ligand ameliorates visual function deficits in a mouse model featuring
several dry AMD phenotypes. Our findings collectively support an age-related compromise in NURR1-
mechanisms in RPE cellular homeostasis. Based on our preliminary data we propose three specific aims to test
the hypothesis that NURR1 represents a therapeutic target for AMD by simultaneously regulating aberrant
RPE barrier function, cellular lipid metabolism, and inflammation, in cells vulnerable in AMD.

## Key facts

- **NIH application ID:** 10233863
- **Project number:** 1R01EY032751-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Goldis Malek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $432,544
- **Award type:** 1
- **Project period:** 2021-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10233863

## Citation

> US National Institutes of Health, RePORTER application 10233863, Nuclear receptor driven mechanisms in aging and AMD (1R01EY032751-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10233863. Licensed CC0.

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