Estrogen and its Receptor in Intraocular Pressure Regulation
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Principal Investigator: Yutao Liu Organization: AUGUSTA UNIVERSITY Fiscal Year: 2024 Award: $383,430 Funding agency: National Eye Institute Abstract The goal of this application is to determine the role of estrogen and its receptors - estrogen receptor 1 (ESR1) and G protein coupled estrogen receptor (GPER1) – in regulating intraocular pressure (IOP) through trabecular meshwork (TM) and Schlemm's canal (SC) endothelial cells. IOP is the primary and only modifiable risk factor for patients affected with primary open-angle glaucoma (POAG) in the clinic. TM and SC modulate majority of aqueous humor outflow resistance in the conventional pathway. Despite the significant research progress in TM/SC outflow dynamics, limited therapeutic targets are available for modulating the conventional outflow. It is necessary to identify novel targets to lower IOP more efficiently in glaucoma patients with progressive visual field loss. Several recent genome-wide association studies have identified >150 IOP- associated genomic loci, which is too many to follow up functionally. Our comprehensive bioinformatics analyses of these IOP-associated genomic loci indicate the enrichment of ESR1-related gene networks among these IOP genes. Factors related with menarche, menopause, and oophorectomy have been associated with POAG. Genetic associations have been identified between sequence variants in estrogen receptor pathway genes and POAG. Estrogen and ESR1-related pathways including aromatase may affect the aqueous humor outflow facility and regulate IOP levels. The presence of estradiol in aqueous humor and ESR1 protein in the TM/SC region further supports the potential role of estrogen and ESR1-related pathways in IOP regulation. Based on our preliminary data on the elevated IOP levels from mouse models with the loss of Esr1 or Gper1 as well as their interaction with Nos3, we hypothesize that activation of estrogen signaling via ESR1 and GPER1 decreases IOP and POAG risk by modulating the turnover of extracellular matrix in the TM and the NO signaling in the SC. We propose to determine the in vivo effects of loss of estrogen signaling via Gper1 (Aim 1) or Esr1 (Aim 2) in murine eyes using tissue-specific knockout mice, and to determine the underlying mechanisms of Gper1 and Esr1-mediated IOP regulation using in vitro primary cell culture models (Aim3). Successful completion of this project will help reveal the critical role of estrogen signaling in aqueous outflow pathway and identify novel therapeutic targets to reduce IOP more effectively for this sight-threatening disease. Terms: <4-vinylcyclohexene diepoxide><65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><ARO><ARO1><Active Follow-up><Affect><Age><Age at Menarche><Aged 65 and Over><Agonist><Anterior><Aquadiol><Aqueous Humor><Aromatase><Bio-Informatics><Bioinformatics><Body Tissues><Bone-Derived Transforming Growth Factor><Bovine Species><CMKRL2><CPV1><CYAR><CYP 19><CYP19><CYP19A1><CYP19A1 gene><Cattle><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cell-Extracellular Matrix><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chemicals><Chemokine Receptor-Like 2><Clinic><Clinical><Common Rat Strains><Cornea><Culturing, in vitro Vertebrate, Primary><Cyclicity><Cytochrome P-450 CYP19><Cytochrome P450 19><Cytochrome P450 19A1><Data><Dimenformon><Diogyn><Diogynets><Disease><Disorder><ECM><ENOS><ERR1 protein><ERRalpha><ERalpha><ERα><ESR1><ESR1 gene><Endogenous Nitrate Vasodilator><Endothelial Cells><Endothelial Nitric Oxide Synthase><Endothelium-Derived Nitric Oxide><Estrace><Estradiol><Estradiol Receptor alpha><Estradiol Receptor α><Estradiol-17 beta><Estradiol-17beta><Estraldine><Estrogen Receptor 1><Estrogen Receptor alpha><Estrogen Receptor α><Estrogen Receptors><Estrogen Synthase><Estrogen Synthetase><Estrogen decline><Estrogens><Extracellular Matrix><Eye><Eye Drops><Eyeball><Eyedrops><Family suidae><Fecundability><Fecundity><Female><Fertility><G Protein-Coupled Estrogen Receptor><G Protein-Coupled Receptor 30><GPER><GPER gene><GPR30><GWA study><GWAS><Genes><Gestation><Glaucoma><Goals><Heterozygote><Histology><Hormone Replacement Rx><Hormone replacement therapy><Hormone use><Human><In Vitro><Individual><Injections><Intracellular Communication and Signaling><Intraocular Fluid><Intraocular Pressure><KO mice><Knock-out Mice><Knockout Mice><L-NAME><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Mechanics><Mediating><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Menarche><Menopause><Mice><Mice Mammals><Milk Growth Factor><Modeling><Modern Man><Monitor><Mononitrogen Monoxide><Murine><Mus><N omega-Nitro-L-arginine Methyl Ester><N(G)-Nitro-L-arginine Methyl Ester><N(G)-Nitroarginine Methyl Ester><NG-Nitro-L-Arginine Methyl Ester><NG-Nitroarginine Methyl Ester><NMR Imaging><NMR Tomography><NOS3><NOS3 gene><NR3A1><Nerve Degeneration><Nerve Fibers><Neuron Degeneration><Nitric Oxide><Nitric Oxide Synthase 3><Nitrogen Monoxide><Nitrogen Protoxide><Nuclear Magnetic Resonance Imaging><Null Mouse><Ocular Hypertension><Ocular Tension><Oophorectomy><Oral Contraceptives><Ovariectomy><Ovocyclin><Ovocylin><P-450AROM><P450AROM><POAG><Pathogenesis><Pathway interactions><Patients><Periodicity><Physiologic><Physiologic Intraocular Pressure><Physiological><Pigs><Platelet Transforming Growth Factor><Post-Menopause><Post-menopausal Period><Postmenopausal Period><Postmenopause><Pregnancy><Primary Cell Cultures><Primary Open Angle Glaucoma><Production><Progynon><Proteins><Rat><Rats Mammals><Rattus><Receptor Protein><Receptor Signaling><Regulation><Research><Resistance><Retina><Retinal Degeneration><Rhythmicity><Risk><Risk Factors><Role><Schlemm's canal><Sight><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Single-Nucleus Sequencing><Staining method><Stains><Steroid Compound><Steroids><Stretching><Structure of sinus venosus of sclera><Subcellular Process><Suidae><Swine><System><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Testing><Therapeutic Estradiol><Therapeutic Estrogen><Thick><Thickness><Tissues><Trabecular Meshwork><Trabecular meshwork structure><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Type III nitric oxide synthase><Variant><Variation><Vision><Visual Fields><Woman><Zeugmatography><above age 65><active followup><after age 65><after menopause><age 65 and greater><age 65 and older><age 65 or older><age > 65><age of 65 years onward><aged 65 and greater><aged 65+><aged ≥65><ages><antagonist G><anterior chamber><aqueous><biological signal transduction><birth control pill><bovid><bovine><contrast imaging><corneal><cow><decline in estrogen><decrease estrogen><decrease in estrogen><degenerative retina diseases><endothelial cell derived relaxing factor><estrogen-related receptor 1><estrogen-related receptor alpha><eye chamber><eye field><female gonadectomy><follow up><follow-up><followed up><following menopause><followup><gene locus><gene network><genetic association><genetic locus><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic location><genomic locus><glaucomatous><heterozygosity><human old age (65+)><in vivo><inhibitor><innovate><innovation><innovative><intra-ocular pressure><malleable risk><mechanic><mechanical><modifiable risk><mouse model><murine model><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neuronal degeneration><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><ocular hypertensive><old age><over 65 years><past menopause><pathway><porcine><post-menopausal><postmenopausal><postmenopausal status><pressure><protective effect><receptor><reduced estrogen><resistant><response><retina degeneration><retinal degenerative><retinal degenerative diseases><sNuc-Seq><sex><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><snRNA sequencing><snRNA-seq><social role><stem><suid><therapeutic target><vinyl cyclohexene dioxide><vinylcyclohexene diepoxide><visual function><whole genome association analysis><whole genome association studies><whole genome association study><≥65 years>