Role of Oxidative Stress in Pathogenesis of Fuchs Endothelial Corneal Dystrophy

氧化应激在福克斯内皮性角膜营养不良发病机制中的作用

• 批准号: 10667428
• 负责人: Ula V. Jurkunas
• 金额: $ 41万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10667428
• 关键词: ATM null mice; Affect; Antioxidants; Apoptosis; Apoptotic; Blindness; CYP1B1 gene; Cell Aging; Cell Cycle; Cell Cycle Arrest; Cell Death; Cell Line; Cells; Cornea; Corneal Endothelium; Corneal edema; DNA; DNA Adduction; DNA Adducts; DNA Damage; DNA Repair; DNA Repair Disorder; DNA Repair Gene; Data; Deposition; Development; Disease; Down-Regulation; Elderly; Endothelial Cells; Endothelium; Enzymes; Estrogen Metabolism; Estrogens; Etiology; Extracellular Matrix; Female; Fuchs' Endothelial Dystrophy; Genes; Genetic; Genotype; Goals; Grant; Human; In Vitro; Incidence; Intervention; Investigation; Keratoplasty; Laboratories; Lead; Light; Link; Liquid substance; M Phase Arrest; M cell; Mesenchymal; Mitochondria; Mitochondrial DNA; Mitosis; Mus; NQO1 gene; Outcome; Oxidants; Oxidative Stress; Oxidative Stress Induction; Pathogenesis; Pathogenicity; Patients; Pharmacological Treatment; Phenotype; Physiological; Predisposition; Resistance; Role; Severities; Sex Differences; Specimen; Tissues; UV induced DNA damage; UVA induced; Ultraviolet Rays; Woman; adduct; age related; aqueous; cell injury; genotoxicity; human old age (65+); in vivo; irradiation; male; mitochondrial dysfunction; mouse model; non-genetic; novel; oxidative DNA damage; oxidative damage; repaired; response; response to injury; senescence; sex; ultraviolet

Project Summary/Abstract Fuchs Endothelial Cornel Dystrophy (FECD), a common age-related dystrophy, which is more prevalent in women, is of unknown etiology. In FECD, corneal endothelial (CE) cell loss is accompanied by abnormal extracellular matrix (ECM) deposition in the form of guttae. Our laboratory was the first to link oxidative DNA damage and mitochondrial dysfunction in FECD pathogenesis. Specifically, we showed that DNA damage, induced by ultraviolet-A (UVA) light, causes FECD in mice. Moreover, the UVA induced CE cell cycle arrest in G2/M phase and cellular senescence. We identified the novel involvement of CYP1B1, the key estrogen- metabolizing enzyme, in sex-dependent differences in CE susceptibility to UVA; and detected greater mitochondrial DNA (mtDNA) damage in female mice. However, the mechanism of the observed greater susceptibility of female mice to UVA-induced DNA damage is unknown. Building upon our previous findings, we propose to investigate if UV light–induced oxidant-antioxidant imbalance leads to senescence and ECM deposition by causing G2/M cell cycle arrest; and if this imbalance causes translocation of CYP1B1 into mitochondria triggering greater estrogen-induced mtDNA damage in females. Gene array analysis revealed downregulation of DNA repair genes in FECD; therefore, we will determine whether this leads to decreased DNA damage repair during G2/M cell cycle arrest, triggering the cells to undergo either senescence or apoptosis. Our study is significant, as the investigation sex-dependent mechanisms involved in oxidative stress-induced cellular damage will provide new treatment targets for FECD. In order to achieve these aims, we will use our newly developed non-genetic mouse model of FECD based on physiologic outcome of CE susceptibility to UVA along with immortalized human CE cell lines, human aqueous fluid, and ex vivo specimens of genotyped FECD donors. Our Specific Aims are: Aim 1: Investigate the role of UVA irradiation in G2/M cell cycle arrest and induction of cellular senescence and ECM deposition in FECD. This aim is based on the hypothesis that DNA damage leads to G2/M phase arrest and induces cellular senescence, which in turn leads to aberrant ECM deposition in the form of guttae in FECD. Aim 2: Determine whether UVA irradiation activates CYP1B1 and induces estrogen metabolism causing preferentially greater DNA damage in females. This aim is based on the hypothesis that higher incidence and severity of FECD in women occurs due to UVA- induced translocation of CYP1B1 into mitochondria, which triggers formation of reactive estrogen metabolites, causing mtDNA damage. Aim 3: Determine the role of DNA damage response and DNA repair during UVA- induced cell cycle arrest in FECD. This aim is based on the hypothesis that DNA repair deficiency during G2/M cell cycle arrest determines whether cells undergo senescence or apoptotic cell death in FECD.

项目总结/文摘

项目成果

Peripheral Endothelial Cell Count Is a Predictor of Disease Severity in Advanced Fuchs Endothelial Corneal Dystrophy.

• DOI: 10.1097/ico.0000000000001292
• 发表时间: 2017-10
• 期刊: Cornea
• 影响因子: 2.8
• 作者: Syed ZA;Tran JA;Jurkunas UV
• 通讯作者: Jurkunas UV

Telomerase immortalization of human corneal endothelial cells yields functional hexagonal monolayers.

• DOI: 10.1371/journal.pone.0051427
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Schmedt T;Chen Y;Nguyen TT;Li S;Bonanno JA;Jurkunas UV
• 通讯作者: Jurkunas UV

UV-A Irradiation Activates Nrf2-Regulated Antioxidant Defense and Induces p53/Caspase3-Dependent Apoptosis in Corneal Endothelial Cells.

• DOI: 10.1167/iovs.16-19097
• 发表时间: 2016-04-01
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4
• 作者: Liu C;Vojnovic D;Kochevar IE;Jurkunas UV
• 通讯作者: Jurkunas UV

Sulforaphane decreases endothelial cell apoptosis in fuchs endothelial corneal dystrophy: a novel treatment.

• DOI: 10.1167/iovs.13-12699
• 发表时间: 2013-10
• 期刊: Investigative ophthalmology & visual science
• 影响因子: 4.4
• 作者: A. Ziaei;T. Schmedt;Yuming Chen;U. Jurkunas

Estrogen genotoxicity causes preferential development of Fuchs endothelial corneal dystrophy in females.

• DOI: 10.1016/j.redox.2023.102986
• 发表时间: 2024-02
• 期刊: REDOX BIOLOGY
• 影响因子: 11.4
• 作者: Kumar, Varun;Deshpande, Neha;Parekh, Mohit;Wong, Raymond;Ashraf, Shazia;Zahid, Muhammad;Hui, Hanna;Miall, Annie;Kimpton, Sylvie;Price, Marianne O.;Price Jr, Francis W.;Gonzalez, Frank J.;Rogan, Eleanor;Jurkunas, Ula, V
• 通讯作者: Jurkunas, Ula, V