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Muscle Tregs in health and disease

Award Number: R01AR070334
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: 05/01/2016
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Muscle Tregs in health and disease - Beyond its primary function of repelling microbial challenges, the immune system plays important roles in safeguarding tissue homeostasis. Macrophages have long been recognized to exercise such secondary functions and, over the past several years, there has been growing interest in the implication of Foxp3+CD4+ regulatory T cells (or Tregs) in homeostatic processes. For example, unique Treg compartments in a number of parenchymal tissues promote local repair/regeneration after acute or chronic injury – even in zebrafish! Skeletal-muscle Tregs serve as a paradigmatic pro-regenerative regulatory T cell population. First reported by our lab in 2012, muscle Tregs increase rapidly after acute injury, differing from lymphoid-organ Tregs in their elevated representation, tissue-adapted transcriptome, distinct – clonally expanded – T cell receptor repertoire, and growth/survival factor dependencies. One intriguing axis, discovered during the last funding-cycle, entails nociceptive neuron production of the peptide, CGRP; which elicits IL-33 production from stromal cells; which, in turn, promotes local Treg accumulation. Muscle Tregs exert multiple influences along the course of tissue repair – on both lymphoid and non-lymphoid cells during both the early, pro-inflammatory, and late, pro-regenerative, phases. This broad range of activities highlights the need to go beyond the current static image of muscle-Treg phenotype and function to obtain a dynamic view spanning the entire process. Temporal single-cell RNAseq data on the muscle-Treg compartment from 1-14 days post-injury (generated during the last funding-cycle) revealed five distinct subtypes that waxed and waned over time: circulating, recently activated, RORγ+, T-bet+ and GATA3+ (or reparative). Our long-term goal is to understand how the five muscle-Treg subtypes integrate with each other and with neighboring lymphoid and non-lymphoid cells to promote muscle regeneration. Our overall hypothesis is that individual subtypes emerge and/or expand to deal with particular biological issues that arise during the repair/regeneration process. In particular, this proposed project aims to: 1. Identify the provenance of RORγ+ skeletal-muscle Tregs. 2. Determine what critical role(s) RORγ+ Tregs play in effective muscle repair/regeneration. 3. Determine whether endogenous CGRP orchestrates increased IL-33 production by muscle MSCs and consequent expansion of the reparative (GATA3+) muscle-Treg subtype. Completion of these studies will provide us with a more accurate and nuanced picture of Treg activities during muscle regeneration. Potential therapeutic applications are many: catastrophic wound healing, exercise- induced damage, age-related sarcopenias, muscular dystrophies, autoimmune myositides and chronic muscle infections.


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 = $335,610 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	10	2/19/2025	NON-COMPETING CONTINUATION	$335,610
														Subtotal = $335,610

Issue Date FY: 2024 ( Subtotal = $361,713 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	9	2/23/2024	NON-COMPETING CONTINUATION	$335,610
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	9	5/21/2024	NON-COMPETING CONTINUATION	$26,103
														Subtotal = $361,713

Issue Date FY: 2023 ( Subtotal = $372,900 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	8	2/17/2023	NON-COMPETING CONTINUATION	$372,900
														Subtotal = $372,900

Issue Date FY: 2022 ( Subtotal = $368,808 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	7	5/4/2022	NON-COMPETING CONTINUATION	$33,529
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	7	2/28/2022	NON-COMPETING CONTINUATION	$335,279
														Subtotal = $368,808

Issue Date FY: 2021 ( Subtotal = $371,800 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	1/25/2021	COMPETING CONTINUATION	$371,800
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	6	5/26/2021	COMPETING CONTINUATION	$124,121
2021	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	5/26/2021	NON-COMPETING CONTINUATION	-$124,121
														Subtotal = $371,800

Issue Date FY: 2020 ( Subtotal = $372,900 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	6/12/2020	NON-COMPETING CONTINUATION	$372,900
														Subtotal = $372,900

Issue Date FY: 2019 ( Subtotal = $372,900 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	2/18/2019	NON-COMPETING CONTINUATION	$372,900
														Subtotal = $372,900

Issue Date FY: 2018 ( Subtotal = $372,900 )
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	5/3/2018	NON-COMPETING CONTINUATION	$37,290
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	2/28/2018	NON-COMPETING CONTINUATION	$335,610
														Subtotal = $372,900

Issue Date FY: 2017 ( Subtotal = $372,900 )
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	6/14/2017	NON-COMPETING CONTINUATION	$37,290
2017	2017	HARVARD COLLEGE, PRESIDENT & FELLOWS OF	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	2/22/2017	NON-COMPETING CONTINUATION	$335,610
														Subtotal = $372,900

Issue Date FY: 2016 ( Subtotal = $372,900 )
2016	2016	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	5/1/2016	NEW	$372,900
														Subtotal = $372,900

Grand Total All Awards = $3,675,331

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Muscle Tregs in health and disease

Award Number: R01AR070334

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: 05/01/2016

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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