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Defining the influence of RA genetic susceptibility factors on T cell antigen specificity and functional state

Award Number: R01AR063759
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/02/2013
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Defining the influence of RA genetic susceptibility factors on T cell antigen specificity and functional state - Project Summary During this past R01 funding period, we have mapped causal effects within the MHC region to specific HLA-DR binding groove amino acid sites, identified >100 rheumatoid arthritis (RA) non- MHC risk alleles across the genome, and have demonstrated that these alleles are largely within CD4+ T cell regulatory elements. If we could define the genetic mechanisms underpinning RA susceptibility, then it may be possible to define therapeutic strategies to abrogate or prevent RA. Central to this is defining the key T cells involved in mediating disease susceptibility – both in terms of their unique TCR sequence features and their pathogenic cell states. Here, we hypothesize that HLA-DR risk alleles act within the thymus to favor selection of “sentinel TCRs”, and that when autoantigens are presented to sentinel TCRs, risk alleles within T cell enhancers alter T cell specific gene regulation, which enables naïve T cells expressing sentinel TCRs to transition into a pathogenic state. We define “sentinel TCRs” as those receptors that bind to citrullinated peptides and trigger the initial autoimmune response. Risk alleles in T cell promoters and enhancers alter regulation of critical T cell genes that regulate the transition of T cells into pathogenic states. Hence, a T cell with a rare “sentinel TCR” can, under the right conditions, trigger the initial autoimmune response, drive a spreading immune response, and initiate persistent joint inflammation. But, the key pathogenic T cell states, sentinel TCRs, and the action of specific causal regulatory T cell alleles are not yet fully defined. Repertoire sequencing to define TCR sequences in blood and tissue, single cell analyses to resolve T cell states, and genetic engineering to interrogate causal T cell alleles and genes represent exciting methodologies that our lab has developed expertise in. In this proposal we seek to build support for this model. First, we will demonstrate that HLA class II HLA RA risk alleles alter TCR repertoire to harbor “sentinel TCRs”, using TCR and genotype data from 300 healthy individuals. Next, we will use polygenic RA risk models to define the key T cell states that RA risk alleles influence with single cell data on surface markers and transcripts in the same 300 individuals. Finally, we will define the molecular mechanisms of non-coding alleles using genomic editing in CD4+ T cells; to this end we will develop and apply strategies to edit primary T cells, sequence DNA to confirm the presence of the desired edit, and obtain RNA and ATAC sequencing data to understand the impact of the edit and confirm the functionality of non- coding alleles.


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 = $448,838 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	3/14/2025	NON-COMPETING CONTINUATION	$416,448
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	10	5/19/2025	NON-COMPETING CONTINUATION	$32,390
														Subtotal = $448,838

Issue Date FY: 2024 ( Subtotal = $479,437 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	9	6/11/2024	NON-COMPETING CONTINUATION	$34,598
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	4/11/2024	NON-COMPETING CONTINUATION	$444,839
														Subtotal = $479,437

Issue Date FY: 2023 ( Subtotal = $494,002 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	3/30/2023	NON-COMPETING CONTINUATION	$494,002
														Subtotal = $494,002

Issue Date FY: 2022 ( Subtotal = $683,931 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	4/22/2022	NON-COMPETING CONTINUATION	$683,931
														Subtotal = $683,931

Issue Date FY: 2021 ( Subtotal = $677,979 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	5/31/2021	COMPETING CONTINUATION	$677,979
2021	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	8/25/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $677,979

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	4/30/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $376,125 )
2018	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	5/15/2018	NON-COMPETING CONTINUATION	$376,125
														Subtotal = $376,125

Issue Date FY: 2017 ( Subtotal = $376,125 )
2017	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	6/14/2017	EXTENSION WITH OR WITHOUT FUNDS	$37,613
2017	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	4/28/2017	EXTENSION WITH OR WITHOUT FUNDS	$338,512
2017	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	4	8/25/2017	EXTENSION WITH OR WITHOUT FUNDS	$291,251
2017	2015	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	3	8/25/2017	NON-COMPETING CONTINUATION	-$291,251
														Subtotal = $376,125

Issue Date FY: 2016 ( Subtotal = $0 )
2016	2015	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	8/2/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $376,125 )
2015	2015	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	7/28/2015	NON-COMPETING CONTINUATION	$376,125
														Subtotal = $376,125

Issue Date FY: 2014 ( Subtotal = $375,948 )
2014	2014	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	7/23/2014	NON-COMPETING CONTINUATION	$375,948
														Subtotal = $375,948

Issue Date FY: 2013 ( Subtotal = $374,885 )
2013	2013	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	8/2/2013	NEW	$374,885
														Subtotal = $374,885

Grand Total All Awards = $4,663,395

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Defining the influence of RA genetic susceptibility factors on T cell antigen specificity and functional state

Award Number: R01AR063759

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/02/2013

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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