# Targeting the inflammatory response in age-related macular degeneration

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $418,750

## Abstract

Neovascular age-related macular degeneration (AMD) is a neuroinflammatory disease that is a
leading cause of blindness in the elderly. While the involvement of photoreceptors in AMD has
been well established, our research will study the less understood role that inflammation plays in
the development of AMD. Our proposal will address this knowledge gap and yield a detailed
understanding of inflammation-associated AMD pathogenesis in humans, in addition to the
identification of potential therapeutic targets and treatments for AMD. Our access to human tissue
with advanced neovascular AMD from the Yale Rapid Autopsy Service and single-cell RNA
sequencing expertise will allow us to perform studies that profile the transcriptome in activated
innate immune cells. Our preliminary data indicate that the critical inflammatory pathways reside
in microglia and monocyte-derived macrophages. Our overarching hypothesis is that functional
changes in the innate system influence neovascularization in AMD, and these changes may be
targeted to halt disease progression. To explore this hypothesis, we propose the following two
specific aims. In Aim 1, we will perform highly parallel single-nucleus transcriptional profiling with
a novel enrichment technique for glia from human eyes with exudative AMD. The primary goal is
to define and interrogate the molecular signature of microglia and macrophages. Our preliminary
data revealed activated microglia in AMD with secretion of the proinflammatory cytokine
interleukin-1b. We hypothesize that there is as upregulation of inflammatory molecules, which is
associated with choroidal neovascularization in AMD. In Aim 2, we will target the pro-
inflammatory cytokines that regulate activation of reactive Müller glia in AMD to identify targetable
pathways to reverse the chronic inflammation in disease. Based on preliminary data, our targets
will include the IL-1b, IL-10, and IL-17 pathways as well as additional ones identified in Aim 1. We
hypothesize that inflammatory molecules are critical for the transformation of homeostatic Müller
glia to a reactive, pro-angiogenic state in AMD. The proposed research plan will provide
unprecedented insight into the molecular mechanisms of AMD progression and has significant
potential to identify novel therapeutic targets for drug discovery. We anticipate that our work will
lead to the development of the first effective therapeutic approaches targeting inflammation,
thereby improving the quality of life for individuals suffering from neovascular AMD.

## Key facts

- **NIH application ID:** 10707366
- **Project number:** 5R01EY034234-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Brian P Hafler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2022-09-30 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10707366

## Citation

> US National Institutes of Health, RePORTER application 10707366, Targeting the inflammatory response in age-related macular degeneration (5R01EY034234-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10707366. Licensed CC0.

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