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Expanded fibroblast subset drives pathology in rheumatoid arthritis

Award Number: R01AR063709
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: 02/01/2015
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Expanded fibroblast subset drives pathology in rheumatoid arthritis - The role of fibroblasts in end organ fibrosis is well established, but insights into their roles in chronic inflammatory diseases in peripheral tissues like rheumatoid arthritis (RA) is still emerging. We identified a highly expanded inflammatory subpopulation of fibroblasts in the sublining region of RA synovial tissue. It accounts for >50% of all fibroblasts in the synovium in RA, but it is a rare population in osteoarthritis (OA). The expanded population is distinguished by high expression of CD90 (Thy1, a sublining marker) and HLA-DR, and the production of IL-6 and many chemokines. We hypothesize that these CD90+DR+IL-6+ fibroblasts are key in driving inflammation directly by secreting inflammatory factors and indirectly by recruiting and activating leukocytes to maintain chronic inflammation. When analyzing single cell RNA-seq data from the RA/SLE Accelerating Medicines Partnership (AMP) Consortium, we found that markers of lining and sublining fibroblasts in synovium were not absolute – but instead represented a gradient in gene expression in trajectory analysis. We found that this transcriptional gradient corresponds to an anatomic spatial gradient in the synovium emanating from blood vessels. Our data suggest that Notch signaling is a dominant driver of the gradient starting with fibroblasts around blood vessels and extending to sublining fibroblasts that express Notch3 receptors and Jagged (Jag)1 Notch ligands. Here, we wish to determine if Notch 3 signaling specifically on fibroblasts drives the spatial pattering and the differentiation of sublining fibroblasts. To accomplish this, in Aim 1 we use mixed cell organoids with endothelial tubules and fibroblasts to compare spatial pattering and differentiation of Notch3 deficient compared to control fibroblasts. In Aim 2, we determine the location of the CD90+DR+ inflammatory cytokine producing fibroblasts and Notch3+ fibroblasts in the synovium and determine which fibroblast population(s) most significantly associate with leukocytes (T cells, B cells and macrophages). In Aim 3 we activate synovial fibroblast lines with inflammatory cytokines that are found in RA, in the presence or absence of Notch ligands. We use flow cytometry, RNA-seq, LDA, and trajectory analyses to compare fibroblast cell states induced in vitro with those found in the synovium in RA. Then, we extend the Notch gradient concept from fibroblast differentiation to how fibroblast-derived Notch ligands activate attached T cell in organoids. Finally, in Aim 4, we determine if targeted, conditional disruption of Notch signaling in fibroblasts or targeted conditional deletion of Notch ligands in fibroblasts prevents inflammatory arthritis in mouse models. Together, these studies will advance our knowledge of how fibroblasts differentiate in RA to become drivers of inflammation and pathology in chronically inflamed synovial tissues, and how they might be targeted therapeutically in murine models.


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: 2024 ( Subtotal = $282,135 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	9/4/2024	NON-COMPETING CONTINUATION	$282,135
														Subtotal = $282,135

Issue Date FY: 2023 ( Subtotal = $290,862 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	8/23/2023	NON-COMPETING CONTINUATION	$290,862
														Subtotal = $290,862

Issue Date FY: 2022 ( Subtotal = $287,953 )
2022	2022	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	8/30/2022	NON-COMPETING CONTINUATION	$287,953
														Subtotal = $287,953

Issue Date FY: 2021 ( Subtotal = $290,862 )
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	9/14/2021	COMPETING CONTINUATION	$290,862
														Subtotal = $290,862

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	6/26/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $385,542 )
2019	2019	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	1/15/2019	NON-COMPETING CONTINUATION	$385,542
														Subtotal = $385,542

Issue Date FY: 2018 ( Subtotal = $385,542 )
2018	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	5/3/2018	NON-COMPETING CONTINUATION	$38,555
2018	2018	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	1/17/2018	NON-COMPETING CONTINUATION	$346,987
														Subtotal = $385,542

Issue Date FY: 2017 ( Subtotal = $385,542 )
2017	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	2/17/2017	NON-COMPETING CONTINUATION	$346,987
2017	2017	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	6/14/2017	NON-COMPETING CONTINUATION	$38,555
														Subtotal = $385,542

Issue Date FY: 2016 ( Subtotal = $385,542 )
2016	2016	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	1/22/2016	NON-COMPETING CONTINUATION	$385,542
														Subtotal = $385,542

Issue Date FY: 2015 ( Subtotal = $385,542 )
2015	2015	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	1/12/2015	NEW	$385,542
														Subtotal = $385,542

Grand Total All Awards = $3,079,522

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Expanded fibroblast subset drives pathology in rheumatoid arthritis

Award Number: R01AR063709

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: 02/01/2015

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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