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Mechanisms of immune-mediated neuronal damage in a mouse model of optic neuritis

Award Number: F30EY036256
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Mechanisms of immune-mediated neuronal damage in a mouse model of optic neuritis - Proposal Summary/Abstract One of the most common yet understudied symptoms of multiple sclerosis (MS) is optic neuritis (ON). ON consists of the autoimmune demyelinating lesions typical of MS occurring within the optic nerve causing inflammation and neuronal damage. This can lead to pain with eye movement and vision loss, and while current therapies targeting the immune system can achieve remission, relapses are common. Most work has been focused on the immune system leaving the neuronal components of ON pathogenesis unknown. This project aims to elucidate mechanisms underlying immune-mediated neuronal damage during ON. Previous work in the Dittel lab discovered that cultured mouse embryonic neurons experienced microtubule destabilization when treated with lytic granules from activated immune cells with cytolytic potential, such as those known to contribute to MS. Microtubule destabilization has been implicated in other neurodegenerative diseases and is often accompanied by tau hyperphosphorylation. Tau is a microtubule stabilizing protein that becomes dysfunctional once hyperphosphorylated. In the mouse model of MS, experimental autoimmune encephalomyelitis (EAE), tau hyperphosphorylation has been observed, further suggesting microtubule destabilization as a key mechanism in immune-mediated neuronal damage. Although ON affects a different population of neurons compared to EAE, we hypothesize the mechanisms of damage are conserved across neuronal populations. This proposal will test that hypothesis and elucidate the contribution of microtubule destabilization on disease development and severity using pharmacologic agents known to alter microtubule structure and stability. Understanding the role of microtubules will provide insight into the downstream effects and functional consequences of the damage, but the cell surface receptor must also be identified to provide a direct link to the immune response. Our work focuses on G-protein coupled receptors that can be activated by components released in lytic granules by activated immune cells. We propose utilizing a combination of pharmacologic inhibition and knock-out animal models to isolate the contribution of a target receptor. All experiments will be assessed using a unique blend of histological and non-invasive imaging techniques, such as optical coherence tomography. This proposal will uncover mechanisms critical to ON development and severity, demonstrate evidence for conserved neuronal signaling machinery activated during immune-mediated damage, and examine the therapeutic potential of hypothesized targets using FDA approved drugs.


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 = $51,628 )
2026	2026	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Vision Research	000	2	1/26/2026	NON-COMPETING CONTINUATION	$51,628
														Subtotal = $51,628

Issue Date FY: 2025 ( Subtotal = $51,628 )
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Vision Research	001	1	12/13/2024	NEW	$0
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Vision Research	002	1	8/18/2025	NEW	$564
2025	2025	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Vision Research	000	1	12/13/2024	NEW	$51,064
														Subtotal = $51,628

Grand Total All Awards = $103,256

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Mechanisms of immune-mediated neuronal damage in a mouse model of optic neuritis

Award Number: F30EY036256

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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