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Metabolic Vulnerability as a Diseased Target for Glaucoma

Award Number: R01EY026662
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2016
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Metabolic Vulnerability as a Diseased Target for Glaucoma - Project Summary Retinal ganglion cell (RGC) axons degenerate after functional decline in glaucoma, a circumstance potentially caused, but certainly exacerbated by, energy deficit, indicating that metabolic dysfunction contributes to glaucomatous degeneration. High intraocular pressure (IOP) in glaucoma results in hypoxia that promotes glycolysis through upregulation of glycolysis-associated genes, but also mitochondrial recycling, and downregulation of genes encoding for oxidative phosphorylation (OxPhos). A critical question is whether RGC metabolic reprogramming from OxPhos to glycolysis is initiated by IOP-associated hypoxia, and whether repeated reprogramming and development of pseudohypoxia underlies the significant energy stress and dysfunction observed in the glaucomatous retina. The long-term goal of this work is to leverage our understanding of retinal metabolism to maintain visual function despite the stressors inherent in glaucomatous neurodegeneration. The overall objective of this proposal is to determine the impact of IOP-mediated damage on retinal and optic nerve head metabolic resilience. Our central hypothesis is that ocular hypertension (OHT)-associated hypoxia transitions into pseudohypoxia, destabilizing neural and glial metabolism and mitochondrial homeostasis, with downstream negative impact on RGCs in the retina and ONH. This hypothesis derives from our recent analysis indicating that mitochondria and availability of energy substrates, both targets of hypoxia-associated regulation, contribute to the metabolic challenges of RGCs. The rationale for the work is that investigating metabolic cooperation and dysfunction in glaucomatous retina will identify new therapeutic targets for a disease that has no mechanism-based interventions. Guided by strong preliminary data, the aims of this proposal will address a critical element of the retinal energy management in glaucoma by revealing 1) whether OHT is the impetus for metabolic reprogramming, followed by adaptation as pseudohypoxia, in the glaucomatous retina; 2) how metabolic coupling is managed among neurons and glia in the normal and ocular hypertensive retina; 3) how RGCs, Müller glia, and ONH astrocytes respond to and manage metabolic challenge on a cell-by-cell basis. Overall, this work will enable us to determine how RGCs, Müller glia, and ONH astrocytes respond metabolically to IOP increase, whether those changes persist long-term, and how we might promote metabolic resilience. The approach is innovative by taking the position that insight will only come from investigating the metabolic dependencies of the primary cell types impacted during the development of glaucoma pathology. In addition, we will apply new cutting-edge approaches to the investigation of mitochondria such as cell- specific mitochondrial isolation followed by metabolomics and co-detection of protein and gene expression through spatial transcriptomics. This proposal is significant because we will reveal mitochondrial-specific metabolic dysregulation amenable to therapeutic intervention.


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 = $0 )
2025	2024	THE UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	000	9	5/29/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $438,815 )
2024	2024	THE UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	001	9	7/29/2024	NON-COMPETING CONTINUATION	$372,295
2024	2024	THE UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	000	8	5/24/2024	SUPPLEMENT FOR EXPANSION	$9,081
2024	2024	THE UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	002	9	8/1/2024	SUPPLEMENT FOR EXPANSION	$57,439
														Subtotal = $438,815

Issue Date FY: 2023 ( Subtotal = $372,295 )
2023	2023	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	000	8	7/18/2023	NON-COMPETING CONTINUATION	$372,295
														Subtotal = $372,295

Issue Date FY: 2022 ( Subtotal = $361,126 )
2022	2022	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	002	7	8/29/2022	NON-COMPETING CONTINUATION	$361,126
2022	2021	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	001	6	3/29/2022	COMPETING CONTINUATION	$82,017
2022	2020	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	000	5	3/29/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$82,017
														Subtotal = $361,126

Issue Date FY: 2021 ( Subtotal = $372,295 )
2021	2021	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	001	6	9/9/2021	COMPETING CONTINUATION	$372,295
2021	2020	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	000	5	9/2/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $372,295

Issue Date FY: 2020 ( Subtotal = $365,000 )
2020	2020	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	003	5	4/1/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$373,697
2020	2020	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	005	5	6/26/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$5,303
2020	2020	UNIVERSITY OF NORTH TEXAS HEALTH SCIENCE CENTER AT FORT WORTH	3500 CAMP BOWIE BLVD	FORT WORTH	TX	76107	TARRANT	USA	Vision Research	001	5	2/11/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$365,000
2020	2019	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 SR 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Vision Research	000	4	2/11/2020	NON-COMPETING CONTINUATION	$0
2020	2019	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 SR 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Vision Research	002	4	4/1/2020	NON-COMPETING CONTINUATION	-$373,697
2020	2019	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 SR 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Vision Research	004	4	6/26/2020	NON-COMPETING CONTINUATION	-$5,303
														Subtotal = $365,000

Issue Date FY: 2019 ( Subtotal = $379,000 )
2019	2019	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 SR 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Vision Research	000	4	3/28/2019	NON-COMPETING CONTINUATION	$379,000
														Subtotal = $379,000

Issue Date FY: 2018 ( Subtotal = $379,000 )
2018	2018	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 SR 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Vision Research	000	3	4/11/2018	NON-COMPETING CONTINUATION	$379,000
														Subtotal = $379,000

Issue Date FY: 2017 ( Subtotal = $379,000 )
2017	2017	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 SR 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Vision Research	000	2	3/20/2017	NON-COMPETING CONTINUATION	$341,100
2017	2017	NORTHEAST OHIO MEDICAL UNIVERSITY	4209 SR 44	ROOTSTOWN	OH	44272	PORTAGE	USA	Vision Research	001	2	6/29/2017	NON-COMPETING CONTINUATION	$37,900
														Subtotal = $379,000

Issue Date FY: 2016 ( Subtotal = $366,100 )
2016	2016	NORTHEAST OHIO MEDICAL UNIVERSITY	P.O. BOX 95	ROOTSTOWN	OH	44272	PORTAGE	USA	Vision Research	000	1	3/10/2016	NEW	$366,100
														Subtotal = $366,100

Grand Total All Awards = $3,412,631

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Metabolic Vulnerability as a Diseased Target for Glaucoma

Award Number: R01EY026662

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2016

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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