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Determining the Role of Cellular Senescence in Chronic Demyelination and Remyelination

Award Number: F31NS147858
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 09/30/2027

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Determining the Role of Cellular Senescence in Chronic Demyelination and Remyelination - Project Abstract Aging is the most significant risk factor for progression of Multiple Sclerosis (MS), a disease characterized by demyelination, or the loss of myelin, and progressive neurological decline. Cellular senescence (CS), a state of irreversible cell cycle arrest, is a key driver of aging and has been implicated in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Emerging evidence suggests that CS also plays a role in MS, with studies indicating that demyelination induces senescent cells in the central nervous system. Markers of CS, including cell cycle arrest proteins (p16INK4a and p21), the lysosomal marker SA-β-gal, and proinflammatory proteins associated with the senescence-associated secretory phenotype (SASP), have been identified in MS pathology. Mouse models of demyelination have also shown evidence of CS following myelin loss; however, it remains unclear why this occurs. I aim to use the chronic cuprizone model of demyelination to explore the relationship between demyelination, CS, and tissue repair. My preliminary data indicate that chronic demyelination drives senescence in the white matter of the brain, particularly in microglia, and these senescent cells are not efficiently cleared during the recovery phase. Based on these findings, I hypothesize that chronic demyelination drives sustained microglia senescence, preventing efficient remyelination and CNS repair. To test this hypothesis, I will perform the following studies: In Aim 1, I will characterize CS in the white matter of both human MS tissue and the chronic cuprizone model using histological and single cell transcriptomic approaches. I will also determine what mechanism induces senescence in microglia following demyelination. In Aim 2, I will determine whether the removal of senescent cells by genetic ablation enhances remyelination and tissue repair. These experiments will provide critical insights into the role of CS in chronic demyelination and MS, advancing our understanding of its impact on disease progression. Furthermore, the findings from this study may support the development of senescence-targeting therapies as a potential treatment strategy for MS patients. My proposed research will provide the opportunity to develop a range of new skills, including bioinformatics, human tissue histology, and primary microglia culture that will be valuable assets in my future career.


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 = $50,114 )
2026	2026	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	8/7/2026	NEW	$0
2026	2026	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/7/2026	NEW	$50,114
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Determining the Role of Cellular Senescence in Chronic Demyelination and Remyelination

Award Number: F31NS147858

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 09/30/2027

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