# Dysregulation of PPARα in RPE degeneration

> **NIH NIH R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2024 · $532,135

## Abstract

PROJECT SUMMARY/ABSTRACT
 Although anti-VEGF therapies have shown impressive benefits for patients with wet form age-related
macular degeneration (AMD), there is no effective treatment for dry AMD, a major unmet clinical need. Retinal
pigment epithelium (RPE) and retina dysfunction and degeneration are the major pathological features in dry
AMD. Deficient mitochondrial function and disturbed lipid metabolism in the RPE are believed to play key
pathogenic roles in these pathologies of dry AMD. However, the molecular mechanism for the dysregulation of
lipid metabolism in the RPE with AMD is elusive. Peroxisome Proliferator-Activated Receptor α (PPARα) is a
transcription factor. It regulates lipid metabolism, and thus, PPARα agonists are used clinically to treat
dyslipidemia. Although our recent study showed that PPARα has a protective role in the retina, the association
of PPARα with the pathogenesis of AMD remains unknown. Our preliminary studies demonstrated that PPARα
levels are down-regulated in the retina and RPE of human donors with dry AMD and in two animal models with
partial AMD phenotypes. Furthermore, activation or expression of PPARα in the RPE partially protected the
retina and RPE against oxidative stress-induced RPE and retina damage. We have demonstrated that PPARα
knockout (KO) alone resulted in age-related ERG decline, retinal degeneration, abnormal RPE cell morphology,
enlarged RPE cell size, impaired RPE barrier, and increased microglia/macrophage adherence to the RPE.
PPARα KO also induced lipid accumulation in the RPE and Bruch’s membrane. Thus, we hypothesize that
PPARα is a major regulator of fatty acid oxidation (FAO) and lipid homeostasis in the RPE, and essential for
maintaining normal structure and function of the RPE and retina. In this project, we will use our newly generated
RPE-specific PPARα conditional KO (PPARα-CKO) mice and transgenic (PPARα-Tg) mice expressing PPARα
in the RPE for the proposed studies. We will analyze changes in RPE barrier function, RPE cell morphology and
cell size, ERG, retinal and photoreceptor cell layer thicknesses, subretinal inflammation, and lipid accumulation
in the RPE and Bruch’s membrane of PPARα-CKO mice under a regular diet or high-fat, cholesterol-rich (HFC)
diet, to reveal if PPARα ablation in the RPE alone will induce retina and RPE pathologies, which will be
accelerated and exacerbated by the HFC diet. We will also determine if PPARα ablation will decrease FAO and
increase glycolysis in the RPE. Proteomic analysis of PPARα-CKO RPE will be performed to identify enzymes
and lipid-binding proteins with changed levels in the RPE of PPARα-CKO mice. Further, we will investigate if
PPARα-Tg mice will show alleviated, while PPARα-CKO mice will show more severe, RPE and retinal injury by
oxidative stress. We will also explore the therapeutic potential of PPARα agonist fenofibrate against RPE and
retinal dysfunction and degeneration in two genetic mouse models with some AMD phenotypes. ...

## Key facts

- **NIH application ID:** 10930060
- **Project number:** 5R01EY034510-02
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Jian-Xing Jay Ma
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $532,135
- **Award type:** 5
- **Project period:** 2023-09-30 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10930060

## Citation

> US National Institutes of Health, RePORTER application 10930060, Dysregulation of PPARα in RPE degeneration (5R01EY034510-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10930060. Licensed CC0.

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