Monday, November 3, 2025 11/3/2025

Binding of Epstein Barr Virus EBNA2 Unifies Multiple Sclerosis Genetic Mechanisms

Award Number: R01NS099068
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: 04/15/2017
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Binding of Epstein Barr Virus EBNA2 Unifies Multiple Sclerosis Genetic Mechanisms - Multiple sclerosis (MS) is a devastating disease of the central nervous system that affects over 2.3 million people worldwide. Current therapies for MS are at best only partially effective, and there is no cure. Improved understanding of MS disease mechanisms would lead to better diagnosis, treatment, and prevention. MS is caused by both genetic and environmental risk factors. Epstein-Barr virus (EBV) is the most consistently replicated environmental factor. Mounting evidence indicates that EBV-infected B cells, and their downstream immunological effects, are key drivers of MS disease processes. Recent work by our group and others implicates the EBV-encoded EBNA2 gene regulatory protein in mechanisms at almost half of the established MS genetic risk loci. In this proposal, we will test the hypothesis that EBNA2-driven allele-dependent alterations to human gene expression lead to distinct B and T cell phenotypes directly contributing to disease processes in MS. Aim 1. Quantification of EBV-specific human gene expression in multiple MS patient demographics. We will expand our cohort to include males and females of European, African, and Asian ancestries. We will measure MS- and EBV-specific human gene expression in these cohorts. Aim 2. Global discovery of EBV- and MS genotype-dependent gene regulatory mechanisms. We will use Massively Parallel Reporter Assays (MPRAs) to systematically identify EBV- and risk allele-dependent gene expression at all MS risk variants in primary B cells with and without EBV infection. We will identify human transcriptional regulators acting with EBNA2, EBNA3C, and/or EBNA-LP at these loci and confirm their allele- dependent actions in MS-derived B cells using cutting-edge functional genomics technologies. We will validate these EBV- and genotype-dependent gene regulatory mechanisms using CRISPR-based genome editing of patient-derived primary B cells at CD37, CD58, ZMIZ1, and other MS risk loci. Aim 3. Discovery of allelic EBV-based mechanisms altering cellular behavior in MS. We will gauge the necessity and sufficiency of EBV and specific MS variants (e.g: CD37, CD58, ZMIZ1) on B cell function using the CRISPR-edited B cells. We will measure impact on B cell receptor signaling, cytokine production, proliferation, and apoptosis. We will use an inducible pluripotent stem cell-derived blood brain barrier (BBB) endothelium model to measure the impact of EBV and MS risk alleles on B cell - BBB interactions. The concept that disease processes might be influenced by virus-controlled, allelic regulatory protein complexes is highly innovative and has never before been demonstrated. Our work for the first time provides mechanistic insight into the established role of EBV in MS through a unified gene by environment model. Comprehensive cataloging, dissection, and understanding of the downstream effects of genetic mechanisms impacted by EBV will be significant because it will provide strong rationale to develop therapies that interfere with these mechanisms, or even vaccines that prevent EBV infection to cure MS and other EBV-related diseases.


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 = $626,014 )
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	4/9/2025	NON-COMPETING CONTINUATION	$626,014
2025	2021	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $626,014

Issue Date FY: 2024 ( Subtotal = $614,354 )
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	5/1/2024	NON-COMPETING CONTINUATION	$44,335
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	3/5/2024	NON-COMPETING CONTINUATION	$570,019
														Subtotal = $614,354

Issue Date FY: 2023 ( Subtotal = $648,175 )
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	4/4/2023	COMPETING CONTINUATION	$648,175
														Subtotal = $648,175

Issue Date FY: 2021 ( Subtotal = $341,377 )
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/7/2020	NON-COMPETING CONTINUATION	$307,239
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	1/12/2021	NON-COMPETING CONTINUATION	$34,138
														Subtotal = $341,377

Issue Date FY: 2020 ( Subtotal = $341,377 )
2020	2020	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	2/11/2020	NON-COMPETING CONTINUATION	$34,138
2020	2020	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/23/2019	NON-COMPETING CONTINUATION	$307,239
														Subtotal = $341,377

Issue Date FY: 2019 ( Subtotal = $342,398 )
2019	2019	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/13/2018	NON-COMPETING CONTINUATION	$342,398
														Subtotal = $342,398

Issue Date FY: 2018 ( Subtotal = $346,991 )
2018	2018	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	5/8/2018	NON-COMPETING CONTINUATION	$34,700
2018	2018	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/6/2017	NON-COMPETING CONTINUATION	$312,291
														Subtotal = $346,991

Issue Date FY: 2017 ( Subtotal = $346,991 )
2017	2017	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/28/2017	NEW	$346,991
														Subtotal = $346,991

Grand Total All Awards = $3,607,677

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Binding of Epstein Barr Virus EBNA2 Unifies Multiple Sclerosis Genetic Mechanisms

Award Number: R01NS099068

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: 04/15/2017

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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