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Principal Investigator: Jian-Xing Jay Ma
Organization: WAKE FOREST UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $474,114
Funding agency: National Eye Institute
Diabetes-induced retinal inflammation plays an important pathogenic role in diabetic retinopathy (DR).
Microglial activation is a key step in retinal inflammation in DR. The molecular mechanism for the microglial
activation in DR remains elusive. Peroxisome Proliferator-Activated Receptor α (PPARα) is a ligand-activated
nuclear receptor and transcription factor. It is known to regulate lipid metabolism, and thus, PPARα agonists are
used clinically to treat dyslipidemia. Two large, prospective clinical studies independently reported a surprising
finding that oral administration of fenofibrate, a PPARα agonist, has robust therapeutic effects on DR in type 2
diabetic patients. However, fenofibrate has not been approved by US FDA for the treatment of DR, as many
questions remain to be addressed. In the prior grant period, we have shown that PPARα levels are decreased
in the retinas of diabetic patients and animal models, and that the therapeutic effect of fenofibrate on DR is
through a PPARα-dependent mechanism. In addition, we have shown that PPARα global knockout (KO)
exacerbated, while activation of PPARα by fenofibrate alleviated, retinal mitochondrial dysfunction in DR models.
Our recent studies reported that PPARα KO alone induced activation of cGAS-STING signaling in retinal and
circulating immune cells. Our preliminary studies showed that PPARα KO resulted in changed morphology and
increased density and migration of microglial cells in the retina. To exclude possible secondary effects of PPARα
global KO and define the function of PPARα in microglia, we have recently generated microglia-specific PPARα
conditional KO (PPARαMCKO) and PPARα transgenic (PPARαMCTG) mice. We found that PPARα ablation in
microglia alone increases the density and migration of microglia, and results in ERG decline, astrocyte
senescence and retinal pericyte loss in diabetes. Therefore, we hypothesize that diabetes-induced down-
regulation of PPARα in microglia results in metabolic dysregulation and subsequently, microglial activation and
inflammation, leading to dysfunction and paracrine senescence of vascular cells and astrocytes through inter-
cellular communications in DR. To address this hypothesis, we will determine if PPARα inhibits microglial
activation and retinal inflammation through regulation of microglial metabolism and mitochondrial function in
diabetes. We will compare microglial cell activation and polarization, metabolic profile, mitochondrial integrity in
diabetic PPARαMCKO and PPARαMCTG mice and controls. We will determine the role of fatty acid transporter
carnitine palmitoyltransferase 1a and fatty acid-binding protein 3 in the regulation of microglial metabolism by
PPARα. We will also investigate how PPARα deficiency in microglia impairs retinal astrocytes and vascular cells
through a disturbed metabolic coupling. We will measure retinal function and structure, vascular permeability
and pericyte density in diabetic PPARαMCKO, PPARαMCTG and controls. The proposed studies will define the
function of PPARα in microglia and explore a new regulatory mechanism for microglial activation in diabetes.
This project will also elucidate the mechanism for the therapeutic effects of fenofibrate on DR.
Terms: <3-hydroxy-3-methylglutaryl-CoA><3-hydroxy-3-methylglutaryl-coenzyme A><Ablation><Address><Adventitial Cell><Age><Agonist><Animal Model><Animal Models and Related Studies><Assay><Astrocytes><Astrocytus><Astroglia><Attenuated><Basal Transcription Factor><Basal transcription factor genes><Bioassay><Biological Assay><Blindness><Blood Vessels><Blood capillaries><Blood-Retinal Barrier><CPT 1><Carnitine Acyltransferase I><Carnitine O-Palmitoyltransferase><Carnitine Palmitoyltransferase><Carnitine Palmitoyltransferase I><Cell Body><Cell Communication and Signaling><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cell to Cell Communication and Signaling><Cell-Cell Signaling><Cells><Clinical><Clinical Research><Clinical Study><Co-culture><Cocultivation><Coculture><Coculture Techniques><Complications of Diabetes Mellitus><Coupling><Cytosol><Diabetes Complications><Diabetes Mellitus><Diabetes-Related Complications><Diabetic Complications><Diabetic Retinopathy><Down-Regulation><Drug Therapy><Drugs><Dysfunction><Dyslipidemias><Endothelial Cells><Exclusion><Fatty Acids><Fenofibrate><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Functional disorder><General Transcription Factor Gene><General Transcription Factors><Genes><Genotype><Genus Hippocampus><Glycolysis><Grant><HMG-CoA><Hortega cell><Immune><Immunes><Impairment><In Situ Nick-End Labeling><Inflammation><Inflammatory><Intermediary Metabolism><Intracellular Communication and Signaling><Ketones><Knock-out><Knockout><Ligands><Lipids><Measures><Medication><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Microglia><Mitochondria><Mitochondrial DNA><Modeling><Molecular><Morphology><Murine><Mus><Neonatal><Nuclear Receptors><Occluding Junctions><Oral><Oral Administration><Oral Drug Administration><PPAR alpha><PPAR-α><PPARalpha><PPARα><Palmitoylcarnitine Transferase><Palmitylcarnitine Acyltransferase><Pathogenicity><Pericapillary Cell><Pericytes><Perivascular Cell><Permeability><Peroxisome Proliferator-Activated Receptor alpha><Peroxisome Proliferator-Activated Receptor α><Pharmaceutical Preparations><Pharmacotherapy><Phenofibrate><Physiopathology><Play><Population><Procetofen><Procetofene><Production><Proteins><Proteomics><Regulation><Reporting><Retina><Retinal Degeneration><Role><Rouget Cells><Seahorse><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Staining method><Stains><Stimulator of Interferon Genes><Structure><TUNEL><Therapeutic Effect><Tight Junctions><Transcription Factor Proto-Oncogene><Transcription factor genes><Transgenic Mice><Transgenic Organisms><Tricor><Type 2 diabetic><Type II diabetic><Vascular Permeabilities><Zonula Occludens><ages><astrocytic glia><attenuate><attenuates><biological signal transduction><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><capillary><carnitine palmitoyltransferase 1><cell sorting><cellular targeting><conditional knock-out><conditional knockout><cyclic GMP-AMP synthase/STING><degenerative retina diseases><density><diabetes><diabetic><diabetic patient><drug treatment><drug/agent><fat metabolism><fatty acid oxidation><fatty acid-binding proteins><flow cytophotometry><gitter cell><glial activation><glial cell activation><hydroxymethylglutaryl-CoA><intercellular communication><intraoral drug delivery><lipid metabolism><mesoglia><metabolic profile><metabolism measurement><metabolomics><metabonomics><microglial cell><microgliocyte><migration><mitochondrial><mitochondrial dysfunction><mitochondrial transcription factor A><model of animal><mtDNA><mtTF1 mitochondrial transcription factor 1><mtTF1 transcription factor><neurotrophic factor><neurotrophin><neutrophin><novel><overexpress><overexpression><paracrine><pathophysiology><perivascular glial cell><prospective><retina degeneration><retinal degenerative><retinal degenerative diseases><scRNA-seq><senescence><senescent><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><terminal nick end labeling><transcription factor><transgenic><vascular><vision loss><visual loss>