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Optineurin dysfunction induces neurodegeneration in normal tension glaucoma by a novel molecular mechanism

Award Number: R01EY032518
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Optineurin dysfunction induces neurodegeneration in normal tension glaucoma by a novel molecular mechanism - PROJECT SUMMARY Normal tension glaucoma (NTG) is characterized by optic neuropathy with progressive retinal ganglion cell (RGC) death and optic nerve (ON) degeneration but in the absence of intraocular pressure (IOP) elevation. All current glaucoma treatments are to lower IOP and are less effective in NTG patients. The primary reasons for the therapeutic vacuum are the limited understanding of the molecular mechanisms of IOP-independent glaucomatous degeneration and the lack of a practical and effective NTG animal model. Causal mutations in the optineurin gene (OPTN) have been found in familial and sporadic NTG. Interestingly, OPTN mutations also cause inherited forms of another CNS axonopathy, amyotrophic lateral sclerosis (ALS), indicating a common degenerative machinery that can be activated by dysfunctional OPTN in vulnerable CNS neuronal populations. However, although OPTN has been extensively studied and its various roles in autophagy, cytokine signaling, and vesicle trafficking have been found, the pathophysiology role of OPTN in CNS neurodegeneration are far from clear. We have recently established a highly efficient NTG mouse model by truncating OPTN gene in RGCs specifically, which presents significant RGCs and ON degeneration within weeks. Using this novel NTG model, we propose to investigate how OPTN mutation causes neurodegeneration in vivo through validating and characterizing OPTN-interacting proteins in RGCs and ON. Through these studies, we will generate essential information to uncover novel molecular mechanisms of glaucomatous neurodegeneration related with OPTN that may be also shared by ALS and other CNS axonopathies, identify novel modifiers of RGC/ON neurodegeneration, and provide valuable tools and animal models to develop neuroprotection therapies.


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: 2026 ( Subtotal = $545,696 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	5	12/5/2025	NON-COMPETING CONTINUATION	$545,696
														Subtotal = $545,696

Issue Date FY: 2025 ( Subtotal = $545,696 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	4	1/15/2025	NON-COMPETING CONTINUATION	$545,696
														Subtotal = $545,696

Issue Date FY: 2024 ( Subtotal = $545,696 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	3	12/11/2023	NON-COMPETING CONTINUATION	$545,696
														Subtotal = $545,696

Issue Date FY: 2023 ( Subtotal = $545,696 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	001	2	2/22/2023	NON-COMPETING CONTINUATION	$54,570
2023	2023	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	2	11/18/2022	NON-COMPETING CONTINUATION	$491,126
														Subtotal = $545,696

Issue Date FY: 2022 ( Subtotal = $545,696 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	1	1/27/2022	NEW	$545,696
														Subtotal = $545,696

Grand Total All Awards = $2,728,480

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Optineurin dysfunction induces neurodegeneration in normal tension glaucoma by a novel molecular mechanism

Award Number: R01EY032518

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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