Fuchs endothelial dystrophy (FECD) is the most common cause of endogenous corneal endothelial degeneration whose primary etiology is unknown. Corneal transplantation is the only currently available measure to restore lost vision. There is mounting evidence that oxidative stress induces damage to corneal endothelium in FECD. Our preliminary studies have identified a decrease in the antioxidant response element (ARE)-driven antioxidants, overexpression of extracellular and stress-related proteins, and an increase in the levels of oxidized mitochondrial DNA in FECD endothelium. Since the underexpressed antioxidants have the common promoter region, antioxidant response element (ARE), we investigated levels of the main ARE- binding transcription factor, nuclear factor-E2-related factor-2 (Nrf2). We detected a decrease in Nrf2 protein level in FECD endothelium. There is, however, limited understanding of how chronic oxidative stress causes molecular and cellular damage in susceptible human corneal endothelial cells and which critical pathways specifically lead to progressive endothelial cell apoptosis and degeneration. It is important to investigate the role of oxidative stress in the pathogenesis of FECD since it opens a new avenue of study that can produce a significant impact on treatment of this blinding condition. The GOAL of the proposed studies is to determine specific cellular mechanisms that can be manipulated to reverse endothelial cell degeneration. These studies are significant because modification of key regulators of oxidant-antioxidant imbalance and resulting cellular damage may ameliorate endothelial cell susceptibility to stress-induced apoptotic cell death that characterizes FECD. Studies will use native samples from FECD patients and normal cadavers for further characterization of the proteomic and genomic differences, and genetic and pharmacotherapeutic manipulation of normal and FECD endothelial cell lines.
Our Specific Aims are:
Aim 1 : Determine the effects of oxidant-antioxidant imbalance seen in FECD on expression of extracellular and stress-related proteins characteristically altered in the dystrophy and endothelial cell apoptosis.
Aim 2 : Determine how diminished Nrf2-regulated defense in FECD corneal endothelium leads to oxidant-antioxidant imbalance by 1) comparing the expression of Nrf2 pathway components between normal and FECD endothelium, and 2) determining whether enhancement of intracellular Nrf2 levels by plasmid transfection and by intracellular Nrf2 stabilizers, such 3H-1,2-dithiole-3- thione (D3T) and tert-butylhydroquinone (tBHQ), can enhance ARE-driven antioxidant expression and ameliorate and reverse the oxidant-induced damage in diseased corneal endothelium.
Aim 3 : Investigate the contribution of oxidative DNA damage on endothelial cell degeneration and apoptosis seen in FECD by 1) comparing levels of mitochondrial and nuclear DNA oxidative damage, 2) correlating the damage to mitochondrial dysfunction, and 3) determining the effects of mitochondria-targeted antioxidants in their ability to ameliorate the oxidative stress-induced cellular damage seen in FECD.

Public Health Relevance

Fuchs endothelial dystrophy (FECD) is the major cause of progressive blindness from corneal endothelial cell death and the second most common cause of corneal transplants done in the elderly (>65 years old) in the U.S. In FECD, corneal endothelium, a layer of cells whose primary function is to maintain corneal transparency, is hypothesized to have a heightened susceptibility to the deleterious effects of oxidative stress resulting in progressive cell death. The research proposed in this application will provide new information of how oxidative stress causes molecular and cellular damage in the susceptible FECD endothelium. Understanding the key regulators of antioxidant defense and oxidative stress-induced cellular damage may facilitate development of pharmacotherapeutic treatment for FECD patients.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Mckie, George Ann
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Schepens Eye Research Institute
United States
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Kocaba, Viridiana; Katikireddy, Kishore Reddy; Gipson, Ilene et al. (2018) Association of the Gutta-Induced Microenvironment With Corneal Endothelial Cell Behavior and Demise in Fuchs Endothelial Corneal Dystrophy. JAMA Ophthalmol 136:886-892
Katikireddy, Kishore Reddy; White, Tomas L; Miyajima, Taiga et al. (2018) NQO1 downregulation potentiates menadione-induced endothelial-mesenchymal transition during rosette formation in Fuchs endothelial corneal dystrophy. Free Radic Biol Med 116:19-30
Richarme, Gilbert; Liu, Cailing; Mihoub, Mouadh et al. (2017) Guanine glycation repair by DJ-1/Park7 and its bacterial homologs. Science 357:208-211
Gupta, Reena; Kinderyte, Ruta; Jacobs, Deborah S et al. (2017) Elimination of Anterior Corneal Steepening With Descemet Membrane Endothelial Keratoplasty in a Patient With Fuchs Dystrophy and Keratoconus: Implications for IOL Calculation. Cornea 36:1260-1262
Syed, Zeba A; Tran, Jennifer A; Jurkunas, Ula V (2017) Peripheral Endothelial Cell Count Is a Predictor of Disease Severity in Advanced Fuchs Endothelial Corneal Dystrophy. Cornea 36:1166-1171
Benischke, Anne-Sophie; Vasanth, Shivakumar; Miyai, Takashi et al. (2017) Activation of mitophagy leads to decline in Mfn2 and loss of mitochondrial mass in Fuchs endothelial corneal dystrophy. Sci Rep 7:6656
Liu, Cailing; Vojnovic, Dijana; Kochevar, Irene E et al. (2016) UV-A Irradiation Activates Nrf2-Regulated Antioxidant Defense and Induces p53/Caspase3-Dependent Apoptosis in Corneal Endothelial Cells. Invest Ophthalmol Vis Sci 57:2319-27
Halilovic, Adna; Schmedt, Thore; Benischke, Anne-Sophie et al. (2016) Menadione-Induced DNA Damage Leads to Mitochondrial Dysfunction and Fragmentation During Rosette Formation in Fuchs Endothelial Corneal Dystrophy. Antioxid Redox Signal 24:1072-83
Katikireddy, Kishore Reddy; Schmedt, Thore; Price, Marianne O et al. (2016) Existence of Neural Crest-Derived Progenitor Cells in Normal and Fuchs Endothelial Dystrophy Corneal Endothelium. Am J Pathol 186:2736-50
Liu, Cailing; Chen, Yuming; Kochevar, Irene E et al. (2014) Decreased DJ-1 leads to impaired Nrf2-regulated antioxidant defense and increased UV-A-induced apoptosis in corneal endothelial cells. Invest Ophthalmol Vis Sci 55:5551-60

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