# Supplement to Promote Diversity in Health-Related Research - Prevention of macular pathophysiology...Parent Grant

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $43,887

## Abstract

The parent grant (R01 EY027785; funding period 2/1/2018 - 1/31-2023) is titled “Prevention of Macular
Pathophysiology Associated with F3 Misfolding”. Age-related macular degeneration (AMD) is the leading cause
of irreversible blindness in people greater than 60 years of age in industrialized countries. Worldwide, it is
estimated that nearly 300 million people will have some form of AMD by 2040. Thus far, no effective treatment
exists for halting dry AMD progression, the form which affects 90% of all AMD patients. The only suggestion for
slowing this form of the disease is to take high-dose vitamin and mineral supplements daily. Emerging evidence
suggests that mutations or alterations in fibulin-3 (F3), a secreted protein of unknown function, plays a prominent
role in influencing the pathogenesis of macular degenerative diseases. One specific example is how an R345W
mutation in F3 causes an early onset macular dystrophy called Malattia Leventinese (ML), which is characterized
by complement activation and production of inflammatory cytokines, as well as sub-retinal pigment epithelium
(RPE) deposits. Furthermore, a D49A mutation in F3 has been associated with development of AMD in patients
with cuticular drusen. In general however, there is a lack of knowledge regarding how these macular
degenerations develop and how they might be influenced by F3. Furthermore, there are no effective treatments
for either ML or the more prevalent disease, dry AMD. Therefore, there is an urgent need to develop a
mechanistic understanding of the underlying causes of AMD-like diseases, such as ML, and to identify new
therapies for them.
The research proposed in this parent grant will; i) test strategies directed at preventing the secretion of misfolded
F3 from cells and evaluate the consequences thereof, ii) employ a novel, conditional approach to regulate
inflammatory signaling downstream of F3 misfolding, and iii) test whether WT F3 is necessary for sub-RPE
deposit formation. Ultimately, at completion of these studies, we hope to have a better understanding of the
molecular basis by which misfolded F3 facilitates inflammation and sub-RPE protein deposition, and to identify
a number of therapeutically-tractable approaches for treating ML. The insight that we gain regarding how
misfolded F3 is involved in triggering inflammation and sub-RPE deposits can likely be applied more broadly to
prevalent retinal diseases such as dry AMD.
Aim 1 of the grant addresses the idea that therapeutically directed regulation of F3 folding and/or secretion may
serve as a way to treat the underlying cause of ML and other diseases caused by F3 misfolding. DaNae will be
focused on making contributions towards developing a deeper understanding of how mutations in F3 lead to
ocular disease, such as AMD and ML, and manipulating cellular quality control mechanisms to prevent F3-
associated disease.

## Key facts

- **NIH application ID:** 10164525
- **Project number:** 3R01EY027785-03S1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** John Douglas Hulleman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $43,887
- **Award type:** 3
- **Project period:** 2018-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10164525

## Citation

> US National Institutes of Health, RePORTER application 10164525, Supplement to Promote Diversity in Health-Related Research - Prevention of macular pathophysiology...Parent Grant (3R01EY027785-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10164525. Licensed CC0.

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