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Ferroptosis in bacterial endophthalmitis: Mechanisms and Therapeutic targeting

Award Number: R01EY027381
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2017
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Ferroptosis in bacterial endophthalmitis: Mechanisms and Therapeutic targeting - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $453,470 )
2025	2025	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Vision Research	000	7	5/29/2025	NON-COMPETING CONTINUATION	$453,470
														Subtotal = $453,470

Issue Date FY: 2024 ( Subtotal = $453,470 )
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Vision Research	001	6	6/7/2024	COMPETING CONTINUATION	$453,470
2024	2021	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Vision Research	000	5	4/3/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $453,470

Issue Date FY: 2021 ( Subtotal = $373,450 )
2021	2021	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Vision Research	000	5	8/20/2021	NON-COMPETING CONTINUATION	$373,450
														Subtotal = $373,450

Issue Date FY: 2020 ( Subtotal = $385,000 )
2020	2020	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Vision Research	000	4	8/6/2020	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2019 ( Subtotal = $385,000 )
2019	2019	WAYNE STATE UNIVERSITY	5057 WOODWARD 13 FLOOR	DETROIT	MI	48202	WAYNE	USA	Vision Research	000	3	8/26/2019	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2018 ( Subtotal = $385,000 )
2018	2018	WAYNE STATE UNIVERSITY	5057 WOODWARD 13 FLOOR	DETROIT	MI	48202	WAYNE	USA	Vision Research	000	2	9/3/2018	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2017 ( Subtotal = $385,000 )
2017	2017	WAYNE STATE UNIVERSITY	5057 WOODWARD 13 FLOOR	DETROIT	MI	48202	WAYNE	USA	Vision Research	000	1	9/19/2017	NEW	$385,000
														Subtotal = $385,000

Grand Total All Awards = $2,820,390

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Ferroptosis in bacterial endophthalmitis: Mechanisms and Therapeutic targeting

Award Number: R01EY027381

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2017

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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