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Bridging the gap between GWAS and mechanism in arthritis

Award Number: R01AR073201
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: 12/01/2018
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Bridging the gap between GWAS and mechanism in arthritis - PROJECT SUMMARY Juvenile idiopathic arthritis (JIA) and rheumatoid arthritis (RA) are inflammatory disease of joints that together affect >1% of the population. Genome-wide association studies (GWAS) have identified >120 non- HLA loci associated with disease risk, each marking a biological pathway confirmed by human population genetics to play a role the pathogenesis of inflammatory arthritis. Unfortunately, pinpointing these mechanisms from GWAS data has proven difficult. GWAS hits mark large segments of DNA, termed haplotypes. Most of these haplotypes contain no SNPs (single nucleotide polymorphisms) or other variants that affect coding, suggesting that most causative polymorphisms are regulatory. Finding regulatory SNPs and the proteins that bind them has proven to be exceptionally difficult, and as a result GWAS in JIA and RA have so far provided limited insight into arthritis biology. In the first cycle of this award, we developed an experimental approach to this problem that allowed us to address this roadblock, identifying pathogenic mechanisms engaged by regulatory variants at TRAF1/C5 and CD28/CTLA4/ICOS. Each solution established a novel pathway not only for arthritis biology but more broadly to mechanisms of immunoregulation, specifically a new feedback loop that limits TNF production and a previously unrecognized role for ICOS in differentiation of T peripheral helper cells. We now propose to use this approach to define new mechanisms of human arthritis mediated through T lymphocytes, testing the hypothesis that common non-coding SNPs uncover novel T cell mechanisms in inflammatory arthritis. Aim I pursues a new variant in the CD28/CTLA4/ICOS that we show regulates not only CTLA4 expression but also Treg abundance; we define the transcription factor that mediates the effect and test whether the impact on Treg abundance is driven through differentiation or stability. Aim II extends these studies first to ANKRD55/IL6ST, a risk locus for both JIA and RA that we implicate in the regulation of CD4+ effector and regulatory T cells; and then more broadly to Tregs, based on a successful massively parallel reporter assay that we will extend using SNP-seq, a novel high-throughput technique developed in the lab that interrogates candidate regulatory variants using enzymatic restriction followed by next- generation sequencing to identify those that bind transcription factors and other regulatory proteins. Together, these studies will extend the successful first cycle of this proposal, leveraging human genetics to define potentially targetable pathways that drive the pathogenesis of JIA and RA.


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 = $633,297 )
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	6	4/10/2025	COMPETING CONTINUATION	$633,297
2025	2025	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	6	4/17/2025	COMPETING CONTINUATION	$0
2025	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	3/26/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $633,297

Issue Date FY: 2023 ( Subtotal = $389,400 )
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	5	11/25/2022	NON-COMPETING CONTINUATION	$350,460
2023	2023	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	003	5	4/24/2023	NON-COMPETING CONTINUATION	$38,940
2023	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	10/22/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$47,743
2023	2021	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	10/22/2022	NON-COMPETING CONTINUATION	-$47,743
														Subtotal = $389,400

Issue Date FY: 2022 ( Subtotal = $401,214 )
2022	2022	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	8/2/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$389,400
2022	2021	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	8/2/2022	NON-COMPETING CONTINUATION	$11,814
														Subtotal = $401,214

Issue Date FY: 2021 ( Subtotal = $381,986 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	5/17/2021	NON-COMPETING CONTINUATION	$27,566
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	1/5/2021	NON-COMPETING CONTINUATION	$354,420
														Subtotal = $381,986

Issue Date FY: 2020 ( Subtotal = $354,420 )
2020	2020	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	12/2/2019	NON-COMPETING CONTINUATION	$354,420
														Subtotal = $354,420

Issue Date FY: 2019 ( Subtotal = $393,800 )
2019	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	11/30/2018	NEW	$393,800
														Subtotal = $393,800

Grand Total All Awards = $2,554,117

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Bridging the gap between GWAS and mechanism in arthritis

Award Number: R01AR073201

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: 12/01/2018

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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