Mechanistic Insights and Therapeutic Potential of the Glutaredoxin (Grx) System in the Lens

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Hongli  Wu
Organization: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
Fiscal Year: 2024
Award: $180,348
Funding agency: National Eye Institute

Summary
The most common cause of vision loss among the elderly is cataract. Oxidative stress is well known to cause
cellular and tissue damage, resulting in age-associated ocular diseases, including cataract. Protein
glutathionylation, the reversible formation of a mixed-disulfide between glutathione and protein thiols, is one of
the major oxidative protein modifications in response to oxidative stress. The glutaredoxin (Grx) system repairs
protein thiols and maintains cellular redox balance. The Grx system has two isoforms, the cytosolic Grx1 (also
known as thioltransferase) and the mitochondrial Grx2. The purpose of this proposal is to study how Grx system
dysfunction may affect the lens redox signaling and its transparency. We hypothesize that Grx1/Grx2 double
deletion may increase the lens susceptibility to ultraviolet (UV) radiation and aging by inhibiting nuclear
factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant response. We also propose that Grx-
activating compounds could protect the lens from UV-induced cataract formation. To prove our
hypotheses, the following Specific Aims are proposed: 1) To identify the role of the Grx system in protecting the
lens from UV radiation and aging using the Grx1/Grx2 DKO mouse as a model. 2) To examine the crosstalk
between the Grx system and the Nrf2-antioxidant pathway. 3) To test if Grx activating compounds could protect
the lens from UV-induced cataract formation. Successful completion of these aims will introduce the Grx system
as a drug target and may lead to the development of Grx-activating compounds as a potential therapeutic for
cataract and other oxidative stress-associated eye diseases.

Terms: <Actinic Rays><Adenosine Triphosphate><Adenylpyrophosphate><Affect><Age><Aging><Antioxidants><Attention><Autoregulation><Binding><Blindness><Body Tissues><Cataract><Cell Communication and Signaling><Cell Signaling><Collaborations><Complex><Crystallins><DIA4><DT Diaphorase><DTD gene><DTD protein><Data><Development><Diaphorase-4><Disulfides><Dose><Drug Targeting><Dysfunction><ERYF1><Elderly><Enzyme Gene><Enzymes><Epithelial Cells><Equilibrium><Erythrocuprein><Euthanasia><Exposure to><Exposure to ultraviolet radiation><Eye diseases><Family><Female><Ferroprotoporphyrin><Functional disorder><GATA Binding Protein 1><GATA-1><GATA1><GATA1 gene><GATA1 protein><GATA1 transcription factor><GF-1 protein><GSSG><Gene Transcription><Genes><Genetic Transcription><Glutathione><Glutathione Disulfide><Grx1 protein><Grx2 protein><H2O2><Heme><Hemocuprein><Heterocyclic Amines><Histology><Homeostasis><Hydrogen Peroxide><Hydroperoxide><Immunoblotting><Individual><Intracellular Communication and Signaling><Isoenzymes><Isoforms><Isozymes><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Mammalian Cell><Measures><Menadione Reductase><Mercaptans><Mercapto Compounds><Mercy Killing><Mice><Mice Mammals><Microscope><Mitochondria><Modeling><Molecular Interaction><Monitor><Morphology><Mothers><Murine><Mus><NAD(P)H Dehydrogenase (Quinone)><NAD(P)H:Menadione Oxidoreductase 1, Dioxin-Inducible 1><NF-E1 erythroid-specific transcription factor><NF-E2 protein><NF-E2 transcription factor><NFE1 protein><NFE2 protein><NMOR1><NQO1><NQO1 gene><Null Mouse><Organ Culture><Organ Culture Techniques><Oxidation-Reduction><Oxidative Stress><Oxidized Glutathione><Oxygenases><Pathway interactions><Persons><Phylloquinone Reductase><Physiological Homeostasis><Physiopathology><Play><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Predisposition><Prevalence><Prevention><Protein Isoforms><Protein Modification><Proteins><Protoheme><RNA Expression><Redox><Risk Factors><Role><Series><Signal Transduction><Signal Transduction Systems><Signaling><Sulfhydryl Compounds><Superoxide Dismutase><Surface Plasmon Resonance><Susceptibility><System><TRX gene><TRX protein><TRX1><TXN gene><Techniques><Testing><Texas><Therapeutic><Therapeutic Agents><Thiols><Thioredoxin><Time><Tissues><Transcription><Transcription Factor GATA1><UV Radiation Exposure><UV exposure><UV induced><UV light><UV radiation><UV radiation-induced><UV rays><Ultraviolet Radiation Related Exposure><Ultraviolet Rays><Ultraviolet radiation exposure><Western Blotting><Western Immunoblotting><Wild Type Mouse><advanced age><age associated><age correlated><age dependent><age linked><age related><age specific><aged group><aged groups><aged individual><aged individuals><aged people><aged person><aged persons><aged population><aged populations><ages><aging population><anti-oxidant enzyme><antioxidant enzyme><balance><balance function><biological signal transduction><cataractogenesis><cataractous lenses><cytocuprein><developmental><enzyme activity><eye disorder><ferroheme><gamma-L-Glu-L-Cys-Gly><gamma-L-Glutamyl-L-Cysteinylglycine><geriatric><globin transcription factor 1><glutaredoxin><glutaredoxin 1><glutaredoxin 2><glutathione peroxidase><high risk><in vitro Organ Culturing><in vitro vertebrate organ culturing><innovate><innovation><innovative><insight><insoluble aggregate><lens><lens protein><lens transparency><lenses><male><meter><mitochondrial><mouse model><murine model><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><nuclear factor-erythroid 1><nuclear factor-erythroid 2><ocular disease><ocular disorder><ophthalmopathy><oxidation><oxidation reduction reaction><oxidative damage><oxidative injury><pathophysiology><pathway><pharmacologic><population aging><preservation><protective effect><protein aggregate><protein aggregation><protein blotting><repair><repair endonuclease><repair enzyme><repaired><response><senior citizen><social role><success><sulfhydryl group><thioltransferase><transcription factor NFE-1><treatment group><trend><ultra violet light><ultra violet radiation><ultra violet rays><ultraviolet exposure><ultraviolet induced><ultraviolet light><ultraviolet light exposure><ultraviolet light induced><ultraviolet radiation><ultraviolet radiation-induced><vision loss><visual loss><wildtype mouse>