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Aberrant DNA Methylation Associated with Repetitive Head Impact Exposure and Chronic Traumatic Encephalopathy

Award Number: F31NS141294
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: 02/01/2025
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Aberrant DNA Methylation Associated with Repetitive Head Impact Exposure and Chronic Traumatic Encephalopathy - Abstract Every year, over 200 million people are exposed to repetitive head impacts (RHI) through contact sports, military service, and domestic violence. RHI-exposure confers risk for developing multiple progressive neurodegenerations, including chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy. The diagnosis of CTE is defined by hyperphosphorylated tau in neurons surrounding blood vessels at the depths of the cortical sulci that typically begins in the dorsolateral frontal cortex (DLFC). Currently, CTE can only be diagnosed at autopsy, and there are no established biomarkers or disease modifying treatments. The development of CTE is associated with increasing years of contact sports participation and with age. Therefore, examination of a community population with small amounts of RHI exposure as well as a group enriched for RHI exposure and CTE may allow for the discovery of changes associated with RHI and CTE pathology development. Epigenome-wide association studies offer a unique opportunity for identification of novel genetic alterations associated with RHI-exposure and CTE. The most extensively studied epigenetic modification is DNA methylation, in which a methyl group is added onto a DNA sequence most commonly at a cytosine that is followed by a guanine, known as a CpG site. This proposal will utilize postmortem human brain tissue from two distinct brain banks: a community-based bank and a brain bank for those with a history of RHI, with the world's largest collection of autopsy-confirmed CTE cases. We hypothesize that RHI-exposure and CTE will have unique DNA methylation signatures resulting in alterations to gene and protein expression. Our preliminary studies identified 13 genes that contained or were nearby multiple aberrantly methylated CpG sites (n=465) that reached genome wide significance for their association with years of contact sports play (proxy used for RHI-exposure) in postmortem human brain tissue. Pathway analyses reveal that the genes containing or close by the aberrantly methylated CpGs are involved in neurogenesis, synaptic organization, and cell signaling. Based on these promising preliminary results, we aim to (1) determine the association of RHI-exposure with aberrant DNA methylation and the downstream alterations on gene and protein expression and (2) to identify distinct DNA methylation signatures in CTE and the downstream alterations in gene and protein expression, and their association to tau accumulation. By elucidating unique epigenetic signatures linked to low level RHI-exposure and to CTE neuropathology, this research will enhance our understanding of the underlying alterations occurring in RHI-exposure and CTE, which may aid in efforts for biomarkers and rational drug design.


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	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/31/2026	NON-COMPETING CONTINUATION	$576
2026	2026	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/8/2026	NON-COMPETING CONTINUATION	$49,538
														Subtotal = $50,114

Issue Date FY: 2025 ( Subtotal = $49,538 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	1	8/11/2025	NEW	$564
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	12/11/2024	NEW	$0
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/11/2024	NEW	$48,974
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	1/28/2025	NEW	$0
														Subtotal = $49,538

Grand Total All Awards = $99,652

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Aberrant DNA Methylation Associated with Repetitive Head Impact Exposure and Chronic Traumatic Encephalopathy

Award Number: F31NS141294

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: 02/01/2025

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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