Saturday, May 17, 2025
5/17/2025
Dysregulation of PPARα in RPE degeneration - 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. The proposed studies will identify a new regulation mechanism for lipid metabolism in the RPE and has the potential to lead to the repurposing of an oral lipid-lowering drug for the treatment of dry AMD.
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