# A mouse model and iPS cells to study hyperactive ABCA1 in the eye in age-related macular degeneration

> **NIH NIH R21** · TEMPLE UNIV OF THE COMMONWEALTH · 2022 · $192,181

## Abstract

Abstract
Age-related macular degeneration (AMD) is a disease of aging that presently has very limited therapeutic
resources. Soft drusen are deposits of protein and lipid between the retinal pigment epithelium (RPE) and
choroidal capillaries in the Bruch's membrane. These deposits are visible in fundus photography as white to
yellow patches in the macula. Their presence is a diagnostic feature of early asymptomatic AMD and a risk
factor for developing late, symptomatic AMD. It was suggested over 25 years ago that drusen interfere with the
flow of water and metabolites between the choroid capillaries and RPE cells and cause RPE cells either to die
as in geographic atrophy and to initiate neovascularization as in wet AMD. However, the source of druse lipid
has remained unknown. At various times, it was proposed that RPE plasma membrane vesicles or
apolipoprotein B-lipoprotein secreted by the RPE was the source of these lesions. Recent genome-wide
association studies pointed to an unexpected culprit: high-density lipoprotein (HDL). It had been known that
apolipoprotein E (apo E) isoform ε4 is protective for AMD. This is the same isoform that does not mediate cell
cholesterol efflux well and is a risk factor in atherosclerosis and Alzheimer's disease. But in AMD it is
protective. The genome-wide association studies additionally implicated ATP-binding cassette transporter
subfamily A member 1 (ABCA1) in AMD. ABCA1 mediates synthesis of HDL from lipid and apoE. ABCA1
alleles that increase plasma HDL cholesterol levels are a risk factor for AMD. Thus, increased production of
HDL is an AMD rick factor. We outline reasons from druse composition and our preliminary data for the RPE
and not plasma origins of HDL that is deposited in drusen. We then propose to test the hypothesis that
hyperactive synthesis of HDL by the RPE contributes to druse formation. The hypothesis is tested in a mouse
model of ABCA1 overexpression in the RPE in Aim 1. The hypothesis is also tested in polarized RPE
monolayer cultures derived from human induced pluripotent stem cells either expressing or missing ABCA1 in
Aim 2. Results of this exploratory project will provide evidence for a larger project into the role of HDL in AMD
pathology.

## Key facts

- **NIH application ID:** 10362536
- **Project number:** 5R21EY032235-02
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Nicholas Lyssenko
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $192,181
- **Award type:** 5
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10362536

## Citation

> US National Institutes of Health, RePORTER application 10362536, A mouse model and iPS cells to study hyperactive ABCA1 in the eye in age-related macular degeneration (5R21EY032235-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10362536. Licensed CC0.

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