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Cellular cross-talk in autoimmune disease

Award Number: P01AI148102
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Cellular cross-talk in autoimmune disease - The overall goal of this P01 is to determine how cells differentiate into states unique to human patients and animal models with autoimmune diseases, how these cells interact with other cells in their environment and how they contribute to disease pathogenesis. Project 1 will focus on the regulation and function of regulatory T cells (Tregs) through the identification of factors and cellular interactions that induce or block Treg acquisition of a dysfunctional AREG+ state in the RA synovium. A key question will be the cross-talk between Tregs and fibroblasts and myeloid cells. Project 2 will determine how fibroblasts differentiate into inflammatory vs invasive states, focusing on the role of the transcription factor, ARID5B, in epigenetic regulation of state transition in RA, and its impact on disease pathology. This project will collaborate with other groups to study the interactions of Treg with fibroblasts via glucocorticoids and AREG and of myeloid cell states with fibroblasts via cytokines. Project 3 will address how plasma cells, which are critical in SLE and RA, adopt diverse states with the potential to interact with other cell types in the tissues via key inflammatory/anti-inflammatory cytokines that impact tissue inflammation, damage and repair. Project 4 will study injury-associated myeloid cells found in patients with LN or RA as well as models of lupus nephritis, and determine their tissue localization, their interactions with fibroblasts, plasma cells and Treg and their roles in autoimmune disease. The computational systems immunology core will carry out analysis of single-cell RNA-sequencing, spatial imaging, lymphocyte repertoire analysis, and genetic variant function. It will also build key data resources that enable cross comparison of RA and SLE tissue cell states. Each project will utilize high-dimensional single-cell genomics in cells or tissues and will be enhanced by computational expertise of the core using integrated and consistent pipelines. It will serve as a cross-disease atlas repository making available all of the cell and molecular data types from RA and SLE collected or analyzed in each project thereby facilitating cell-cell interactions and cross-disease similarities and differences. Our capacity to study the interactions among Tregs, fibroblasts, plasma cells and myeloid cells, which are central to the immunopathology of these diseases, depends upon synergistic interactions enabled by the program project mechanism. If successful, this P01 will enable an integrated multicellular view of Treg dysfunction and recovery, fibroblast-mediated tissue inflammation and damage, plasma cell-regulated inflammation, damage and repair, and the impact of injury-induced myeloid states on tissue homeostasis. The identification of cell states, pathways and cell-cell interactions should provide valuable targets for future therapies for lupus nephritis and rheumatoid arthritis.


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 = $2,412,120 )
2026	2026	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	6	6/1/2026	COMPETING CONTINUATION	$2,412,120
2026	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	5	5/29/2026	NON-COMPETING CONTINUATION	$0
2026	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	3/10/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $2,412,120

Issue Date FY: 2025 ( Subtotal = $2,491,765 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	4/17/2025	NON-COMPETING CONTINUATION	$2,491,765
														Subtotal = $2,491,765

Issue Date FY: 2024 ( Subtotal = $2,491,765 )
2024	2024	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	4/2/2024	NON-COMPETING CONTINUATION	$2,491,765
														Subtotal = $2,491,765

Issue Date FY: 2023 ( Subtotal = $2,491,765 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	3/27/2023	NON-COMPETING CONTINUATION	$2,491,765
														Subtotal = $2,491,765

Issue Date FY: 2022 ( Subtotal = $2,491,765 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	3/29/2022	NON-COMPETING CONTINUATION	$2,491,765
														Subtotal = $2,491,765

Issue Date FY: 2021 ( Subtotal = $2,511,008 )
2021	2021	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	6/11/2021	NEW	$2,511,008
														Subtotal = $2,511,008

Grand Total All Awards = $14,890,188

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Cellular cross-talk in autoimmune disease

Award Number: P01AI148102

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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