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Optic nerve head astrocyte sensitivity to glaucomatous insult

Award Number: R01EY036880
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2025
PERIOD OF PERFORMANCE END DATE: 02/28/2030

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Optic nerve head astrocyte sensitivity to glaucomatous insult - PROJECT SUMMARY/ABSTRACT Elevated intraocular pressure (IOP) is a major risk factor for optic nerve damage in glaucoma. Perplexingly, optic nerve sensitivity to IOP varies widely across individuals. The overarching goal of this proposal is to investigate fundamental mechanisms that drive optic nerve sensitivity to IOP. IOP elevation induces pathologic biomechanical strains on the optic nerve head (ONH). Our previous work identified astrocytes within the ONH as key sensors of IOP-related biomechanical strain. We recently engineered a 3D hydrogel system to precisely quantify the response of ONH astrocytes to pathologic biomechanical strains. Our preliminary data using this innovative system support that pathologic biomechanical strains induce similar ONH astrocyte dysfunction in vitro as IOP elevations do in vivo. They undergo process retraction and dysregulate oxidative phosphorylation and mitophagy pathways. We additionally identified the mechanosensitive channel Piezo1 as a key sensor of biomechanical strain. In the current proposal, we aim to use a combination of cutting-edge 3D bioengineering tools, transgenic animal models, and ex vivo donor ONH tissue, to test our central hypothesis: Transient biomechanical strains prime ONH astrocytes to develop greater glaucomatous morphologic and mitochondrial dysfunction via Piezo1 activation. We propose the following specific aims: Aim 1: Determine to what extent ONH astrocytes integrate transient biomechanical strains to predispose to future glaucomatous dysfunction. Aim 2: Determine if transient biomechanical strains predispose ONH astrocytes to lactate dysregulation and mitochondrial dysfunction. Aim 3: Determine if ONH astrocyte Piezo1 regulates ONH astrocyte sensitization and RGC viability in response to transient biomechanical pre-strains. The proposed experiments will advance our understanding of glaucomatous optic nerve damage by (i) determining if astrocytes within the ONH regulate optic nerve sensitivity to IOP, (ii) exploring a mechanistic link between biomechanical strain, metabolic insufficiency, and ONH susceptibility in glaucoma, and (iii) investigating if inhibiting mechanosensory pathways will prevent ONH astrocyte priming by biomechanical strain.


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 = $389,995 )
2026	2026	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Vision Research	000	2	4/3/2026	NON-COMPETING CONTINUATION	$389,995
														Subtotal = $389,995

Issue Date FY: 2025 ( Subtotal = $387,428 )
2025	2025	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	750 E ADAMS ST	SYRACUSE	NY	13210	ONONDAGA	USA	Vision Research	000	1	2/25/2025	NEW	$387,428
														Subtotal = $387,428

Grand Total All Awards = $777,423

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Optic nerve head astrocyte sensitivity to glaucomatous insult

Award Number: R01EY036880

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2025

PERIOD OF PERFORMANCE END DATE: 02/28/2030

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