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Regulating host neural activity to improve retinal ganglion cell replacement therapies

Award Number: K99EY036122
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 02/01/2025
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Regulating host neural activity to improve retinal ganglion cell replacement therapies - Project Summary Glaucoma is a neurodegenerative disease that causes irreversible vision loss due to the death of retinal ganglion cells (RGCs). Prior studies, including ours, reveal that while cell transplantation can replace lost RGCs, most donor RGCs still fail to integrate within the host retina. Since the mammalian retina cannot regenerate naturally, we must provide exogenous cues to control the retinal microenvironment and support RGC regeneration. Previously, I demonstrated that introducing chemokine gradients and inhibiting subtype-specific avoidance mechanisms can improve the structural integration of donor RGCs in the retina. However, not all donor RGC structural integrate, and there is limited evidence of functional donor-host neuron connectivity, suggesting unknown factors limit donor RGC integration. I hypothesize that neural activity, a major regulator of plasticity, is potentially limiting donor neuron integration. Therefore, I aim to investigate the role of neural activity in RGC integration in the retina to improve functional connections with existing visual neurocircuitry. Furthermore, by establishing a model for manipulating host RGC neural activity, we can selectively inhibit neural activity during electrophysiological recordings to distinguish donor RGC activity from host neurons and quantify functional integration at scale. Using this same endogenous RGC inactivation model, we can decouple neural activity from cell death (Aim 1) and inhibit retinal neuron activity during and after transplantation (Aim 2) to investigate the role of neural activity in host and donor visual neural circuit remodeling. Aim 1 will focus on retinal remodeling following a period of RGC inactivation, while Aim 2 will investigate if inhibiting host neural activity can improve donor RGC structural and functional integration. The K99 phase will focus on model characterization and the role of neural inhibition on RGC structural characteristics, with the R00 phase extending this focus to those same RGCs but to their functional characteristics. Altogether, by controlling host neural activity and transplanting donor neurons in my endogenous RGC inactivation model, we aim to improve RGC replacement therapies and quantify the remodeling of host and donor visual neural circuits. I aim to build upon this research project to establish a strong foundation for my independent research program on neural plasticity in the visual system. During the K99 phase, I will expand my expertise in regenerative ophthalmology to accomplish my aims by studying visual neural circuit remodeling. This work will dovetail into my independent research program focusing on donor-host neural connectivity. The training portion of this proposal will take place at Schepens Eye Research Institute of Mass Eye and Ear, which offers unprecedented access to research equipment and faculty expertise to assist in accomplishing my goals.


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 = -$2,171 )
2026	2025	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	1	6/15/2026	NEW	-$2,171
2026	2025	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	1	6/8/2026	NEW	$0
														Subtotal = -$2,171

Issue Date FY: 2025 ( Subtotal = $132,597 )
2025	2025	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	1	1/29/2025	NEW	$132,597
														Subtotal = $132,597

Grand Total All Awards = $130,426

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Regulating host neural activity to improve retinal ganglion cell replacement therapies

Award Number: K99EY036122

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 02/01/2025

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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