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Principal Investigator: Ashok Kumar
Organization: WAYNE STATE UNIVERSITY
Fiscal Year: 2024
Award: $453,470
Funding agency: National Eye Institute
Project Summary
Bacterial endophthalmitis is a vision-threatening complication of eye surgeries and ocular trauma. The vision
loss in endophthalmitis occurs due to uncontrolled inflammation-mediated retinal tissue damage. The long-term
goal of our research has been to study the pathobiology of endophthalmitis and identify potential therapeutic
targets for treatment. Our recent work using transcriptomics and metabolomics has uncovered the importance
of cellular metabolism in regulating the innate immune response during experimental Staphylococcus aureus
(SA) endophthalmitis. Notably, we observed significant impairment in the antioxidant glutathione peroxidase 4
(GPX4) signaling, which plays a crucial role in reducing lipid peroxide accumulation and preventing ferroptosis
cell death. Ferroptosis, a newly discovered form of cell death linked to iron overload, is regulated by GPX4.
Surprisingly, the role of the GPX4/Ferroptosis axis in ocular infections has remained unexplored. Based on our
findings, we hypothesize that reduced GPX4 levels, combined with elevated iron levels during endophthalmitis,
contribute to ferroptotic cell death in the retina. In support, our preliminary data show, downregulation of GPX4,
an increased labile iron pool, excessive lipid peroxidation, and induced expression of ACSL4 in SA-infected
retina and cultured cells. Here, we will employ mouse genetic tools and pharmacological interventions to
elucidate the mechanisms underlying impaired GPX4 signaling (Aim 1), investigate the role of ACSL4 as the
final executor of ferroptosis (Aim 2), and test potential of nanoformulations to enhance GPX4 levels and reduce
ferroptosis as a novel approach to treat bacterial endophthalmitis (Aim 3). The knowledge gained from this
study into the regulation of ferroptosis during endophthalmitis and the development of therapeutic strategies
could have a significant impact not only on ocular infections but also on other eye diseases involving
ferroptosis. Ultimately, our work aims to contribute to the advancement of therapeutic interventions in the field,
offering new hope for preserving vision and improving outcomes in patients affected by these conditions.
Terms: <Acid-Thiol Ligases><Acyl CoA Synthetases><Acyl Coenzyme A Synthetases><Affect><Age><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antioxidants><Apoptosis><Apoptosis Pathway><Attenuated><Bacteria><Blindness><Body Tissues><Butyrates><Cell Body><Cell Communication and Signaling><Cell Death><Cell Death Induction><Cell Signaling><Cells><Co A Ligases><Coenzyme A Ligases><Coenzyme A Synthetases><Communicable Diseases><Complement><Complement Proteins><Complication><Cultured Cells><Cystine><DNA Therapy><Data><Deferoxamine><Deferoxamine B><Deferoximine><Deferrioxamine B><Desferioximine><Desferrioxamine><Desferrioxamine B><Desferroxamine><Development><Down-Regulation><Endophthalmitis><Enzyme Gene><Enzymes><Exhibits><Eye Infections><Eye Injuries><Eye diseases><Family member><Fatty Acid Hydroperoxides><Fe chelation><Fe element><Fe overload><Funding><Gene Transfer Clinical><Genetic Intervention><Glutamates><Goals><HETE><Hydroxyeicosatetraenoic Acids><Impairment><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Inflammatory><Inflammatory Response><Innate Immune Response><Intermediary Metabolism><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Iron><Iron Chelation><Iron Overload><Iron chelator><KO mice><Knock-out Mice><Knockout Mice><Knowledge><L-Cystine><L-Glutamate><Link><Lipid Hydroperoxide><Lipid Peroxidation><Lipid Peroxides><Lipoperoxides><Mediating><Mediator><Metabolic Processes><Metabolism><Mice><Mice Mammals><Miscellaneous Antibiotic><Murine><Mus><Null Mouse><Ocular Infections><Ocular Injury><Operative Procedures><Operative Surgical Procedures><Ophthalmia><Ophthalmologic Surgical Procedures><Ophthalmological Surgery><Ophthalmological Surgical Procedures><Oxidative Stress><Patients><Play><Predisposition><Programmed Cell Death><Property><Reduced Glutathione><Regulation><Research><Resolution><Retina><Risk><Role><S aureus><S. aureus><S. aureus infection><Se element><Selenium><Severities><Sight><Signal Transduction><Signal Transduction Systems><Signaling><Staph aureus><Staph aureus infection><Staphylococcus aureus><Staphylococcus aureus infection><Surgical><Surgical Interventions><Surgical Procedure><Susceptibility><System><Testing><Therapeutic><Therapeutic Intervention><Tissues><Transgenic Mice><Vancomycin><Vision><Work><age associated><age correlated><age dependent><age linked><age related><age specific><ages><antiporter><attenuate><attenuates><bacterial endophthalmitis><biological signal transduction><complementation><developmental><elderly patient><eye disorder><eye surgery><eye trauma><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genomic therapy><glutamatergic><glutathione peroxidase><improved outcome><infected with S. aureus><infected with Staph aureus><infected with Staphylococcus aureus><infection risk><inhibitor><insight><intervention therapy><interventional strategy><intravitreal injection><lipid mediator><lipid peroxide><lipidomics><metabolism measurement><metabolomics><metabonomics><mouse genetics><nano formulation><nano particle><nano-sized particle><nanoformulation><nanoparticle><nanosized particle><necrocytosis><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><ocular disease><ocular disorder><ocular trauma><older patient><ophthalmopathy><pathogen><pharmacologic><preservation><prevent><preventing><resolutions><response><social role><surgery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic agent development><therapeutic development><therapeutic target><thiokinase><tool><transcriptomics><vision loss><visual function><visual loss>