Tuesday, July 1, 2025 7/1/2025

Defining mechanisms of disease and repair in a viral model of multiple sclerosis

Award Number: R35NS116835
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Defining mechanisms of disease and repair in a viral model of multiple sclerosis - Abstract: An important unmet clinical need for patients with the demyelinating disease multiple sclerosis (MS) is an effective method for promoting remyelination that can ameliorate clinical symptoms associated with demyelination and restore motor function while limiting immune cell infiltration into the CNS. The long-term objectives of this research proposal are to i) define how chemokine signaling controls neuroinflammation and disease progression, ii) assess the effects of chemokine signaling in regulating oligodendrocyte progenitor cell (OPC) maturation and remyelination, iii) further characterize how engrafted human and mouse neural progenitor cells enhance axonal integrity, promote remyelination and influence neuroinflammation/demyelination, iv) define mechanisms by which microglia restrict the severity of demyelination and influence remyelination. To accomplish these goals, we will use a well-accepted pre-clinical animal models of MS. For over 20 years, my laboratory has used intracranial infection of susceptible C57BL/6 mice with the neuroadapted JHM strain of mouse hepatitis virus (JHMV) as a model of viral-induced demyelination to study molecular and cellular events controlling neurioinflammation, demyelination, and remyelination. Proposed experimental procedures that will aid in accomplishing our research goals will include genetic approaches through generation of mice in which targeted genes are either selectively induced/ablated to assess effect on disease progression and repair, CRISPR technology to ablate specific target genes in NPC cultures, single cell and nuclear RNA sequencing on immune cells and resident CNS cells and use of 2-photon (2P) microscopy to visualize axonal damage/repair and remyelination. Collectively, we believe our experimental goals outlined in this proposal will provide new insight into the pathogenesis of MS as well as identify new targets for therapeutic intervention to impede disease progression and promote remyelination.


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 = $871,109 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	5/2/2025	NON-COMPETING CONTINUATION	$871,109
2025	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	3/14/2025	NON-COMPETING CONTINUATION	$0
2025	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/3/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $871,109

Issue Date FY: 2024 ( Subtotal = $846,461 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/8/2024	NON-COMPETING CONTINUATION	$846,461
														Subtotal = $846,461

Issue Date FY: 2023 ( Subtotal = $874,084 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/13/2023	NON-COMPETING CONTINUATION	$874,084
														Subtotal = $874,084

Issue Date FY: 2022 ( Subtotal = $875,447 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/8/2022	NON-COMPETING CONTINUATION	$875,447
														Subtotal = $875,447

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	9/24/2021	NEW	$0
2021	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/11/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $697,256 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/24/2020	NEW	$697,256
														Subtotal = $697,256

Grand Total All Awards = $4,164,357

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Defining mechanisms of disease and repair in a viral model of multiple sclerosis

Award Number: R35NS116835

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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