Differentiation of immune cells and fibrobalsts in inflamed tissue in RA and SLE

Active Project Grant Awarded Last action

Award ID
P01AI148102
Recipient
Awarding agency
Obligated
$14,890,188

Award facts

Assistance listing
93.855 Allergy and Infectious Diseases Research
Completion date 55% complete
Originally
Place of performance
Boston, MA 02115, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are different diseases clinically and the most important tissue damage occurs in joints and kidneys, respectively. Yet, both SLE and RA share a central common theme of adaptive T and B cell interactions that result in autoantibody production. Both tissues develop chronic inflammatory reactions that also include myeloid cell populations, neutrophils and other innate leukocytes. The two diseases cluster in families and share a number of closely related risk alleles suggesting related immune mechanisms. Developing targeted therapies for lupus has been frustrating and while a number of therapies can reduce disease activity in RA, a large unmet need exists in the form of TNF inadequate responders; and there is no cure. Based on the RA/SLE AMP consortium, single cell RNA-SEQ and cytof analysis has phenotypically and transcriptionally identified many unexpected cell types and cell states present in the inflamed kidney in lupus nephritis and RA synovitis. Here, we select a set of important cell populations specific to, or highly enriched in, the involved tissues in both diseases. Given the importance of B cells and antibody production, we focus on the novel subset of age (or autoimmunity) associated B cells (ABC B cells) and B helper T cells including both T follicular helper (TFH) and the recently discovered T peripheral helper (TPH) T cells in project 1. The project focuses on defining the relationship of ABC to other B cell populations and examines the role of TPH and TFH cells in driving ABC B cells and their cross-talk. ABC B cells and TPH/TFH cells are enriched in both lupus kidney and RA synovium allowing their comparison across diseases. Project 2 examines novel macrophage inflammatory states found in lupus kidney and seeks to define the main activating factors and transcription factors that drive cell state changes to achieve the inflammatory CM4 state that predominates in nephritis. Project 3 examines the fibroblastic stroma that drives inflammation in RA. A population of inflammatory sublining CD90+DR+ fibroblasts is profoundly expanded in RA and implicated in perpetuating inflammation. Project 3 examines the role of a notch gradient and notch signaling in driving the differentiation and activation of this population in synovium and kidney and its role in inflammatory arthritis. All 3 projects interact to examine the cell types of interest across diseases, to determine which cells are interacting most closely by integrated imaging analysis. By utilizing the synchronized expert pipelines of the computational systems immunology core for single cell RNA-SEQ and image analysis, the data gathered from both diseases and tissues can be effectively compared. All 3 projects focus on determining the drivers and transitions that yield the important cell states that have been discovered directly in the involved tissues. Together, the program will provide new insights into the tissue immunopathology in these human autoimmune diseases and help to unfold new avenues for therapeutic intervention.

Transactions

Action Obligated Date
Amendment $2,412,120
Amendment 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… $0
Amendment $0
Amendment 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… $0
Amendment $2,491,765
Amendment $2,491,765
Amendment $2,491,765
Amendment $2,491,765
Original award $2,511,008

Subawards

Subrecipient Amount Awarded
The Broad Institute, Inc. As the Subaward PI and overall PD/PI, Dr. Nir Hacohen, shall provide scientific, administrative, and technical leadership in support of the multi-PI P01… $471,504
The Feinstein Institutes For Medical Research Under a subcontract executed between Brigham and Women’s Hospital and The Feinstein Institutes for Medical Research and as the subcontract PI, Dr. Diamond… $440,744
University Of Birmingham Subrecipient will undertake provision of at least five tissue samples per year in a format suitable for cellular disaggregation, alongside tissue sections for… $100,000
The Feinstein Institutes For Medical Research In this project, we will characterize age/autoimmunity associated B cells (ABCs) in kidney and synovium of patients with systemic lupus and rheumatoid arthritis… $2,016,386
The Broad Institute, Inc. The Broad site of the Computational Systems Immunology will be based in the Imaging Platform, and will provide key computational support to analyze imaging data… $756,849
The Broad Institute, Inc. The Broad will investigate the states, differentiation, localization and functional roles of monocytes in lupus and rheumatoid arthritis. $2,260,030

Quick answers

Who received award P01AI148102?

P01AI148102 was awarded to Brigham & Womens Hospital Inc. by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on June 11, 2021.

How much is award P01AI148102 worth?

$14,890,188 has been obligated on P01AI148102.

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