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The mechanotranscriptome of the optic nerve head following acute experimental ocular hypertension in living human eyes

Award Number: R01EY035053
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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The mechanotranscriptome of the optic nerve head following acute experimental ocular hypertension in living human eyes - Glaucoma is one of the leading causes of irreversible blindness for which the lowering of intraocular pressure (IOP) is the only proven treatment. Since elevated IOP is a critical risk factor for glaucoma, several animal models have been developed to study the cellular, vascular, and electrophysiologic responses of the retina to acute IOP elevation. While these models have elucidated the relationship between ocular perfusion and retinal function as well as many of the cellular pathways activated in response to acute IOP related exposure, there are significant differences in optic nerve structure and composition across species, limiting the translation of these findings to the human disease. This project will study the impact of IOP elevation in the living human eye for the first time by utilizing the unique resources developed by the Living Eye Project. This project provides experimental access to the human eye in vivo in research-consented brain-dead organ donors prior to organ procurement. Following enucleation, the Living Eye Project provides access to the same eyes for ex vivo analysis of cellular and tissue responses. Our principal hypothesis is that acute IOP elevation results in deformation of the optic nerve head (ONH), and this deformation drives mechanosensitive mechanisms within the lamina cribrosa (LC) and peripapillary sclera that initiate pathologic remodeling of the LC, which injures the axons of retinal ganglion cells traversing this mechanically dynamic region. These mechanosensitive pathways will be characterized using spatial transcriptomics for the first time in the human eye alongside immunohistochemistry and protein analysis. We predict that increased IOP initiates a profibrotic, inflammatory phenotype and transcriptomic alterations that regionally colocalize with the connective tissue density within the LC and are associated with the magnitude of IOP-induced deformation of the ONH measured in vivo. Our unprecedented opportunity to measure structural and biomechanical parameters of the human ONH in vivo and perform ex vivo evaluation of the cellular mechanobiology of the same tissues will provide the first direct experimental link between ONH mechanical strain and the molecular and cellular responses of ONH tissues that drive remodeling, which is critical to the development and progression of glaucomatous optic neuropathy. Defining this “mechanotranscriptome” in the human ONH will critically assess the translational value of animal models for studying mechanotransduction as well as define the human cellular and molecular mechanisms of ONH remodeling needed to guide the development of novel therapeutics designed to enhance the resilience of the ONH to pressure-related stress.


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 = $524,518 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Vision Research	001	3	9/15/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$524,518
2025	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	000	2	9/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $524,518

Issue Date FY: 2024 ( Subtotal = $601,234 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	000	2	5/31/2024	NON-COMPETING CONTINUATION	$601,234
														Subtotal = $601,234

Issue Date FY: 2023 ( Subtotal = $572,344 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	000	1	5/26/2023	NEW	$572,344
														Subtotal = $572,344

Grand Total All Awards = $1,698,096

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The mechanotranscriptome of the optic nerve head following acute experimental ocular hypertension in living human eyes

Award Number: R01EY035053

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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