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The function of mTORC1/Stat3 signaling in the regulation of fibrovascular scar formation during tendon healing

Award Number: R01AR079486
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: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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The function of mTORC1/Stat3 signaling in the regulation of fibrovascular scar formation during tendon healing - Project Summary/Abstract Tendon injuries are challenging clinical problems due to slow, incomplete healing with fibrovascular scar formation, which reduces tendon function and causes chronic complications such as pain and tendon ruptures. The limited understanding of the regulatory mechanisms underlying fibrovascular scar formation is a significant gap in knowledge, hindering the development of effective treatment modalities for tendon diseases. Fibrovascular scar tissue is characterized by a disorganized extracellular matrix (ECM) with high cellularity and neovascularization. Therefore, there is a critical need to understand the key factors regulating tendon cells and ECM maturation during tendon healing to develop regenerative medicine. Recent studies have demonstrated that mTORC1 (mechanistic target of rapamycin complex 1) signaling is a critical regulator for postnatal tendon maturation and is associated with pathogenic tendon conditions such as fibrotic adhesion of flexor tendon, fatty infiltration after rotator cuff tears, and human tendinopathy. However, the function of mTORC1 in fibrovascular scar formation and its downstream molecular mechanisms are not known. Stat3 (signal transducer and activator of transcription 3) is involved in fibrotic scar formation in multiple tissues and is known as a downstream target of mTORC1 signaling in cancer cells. However, there is no reported evidence showing that Stat3 mediates the function of mTORC1 in fibrovascular scar formation in tendons. Our overall objective is to define the function of the mTORC1/Stat3 signaling cascade in fibrovascular scar formation and evaluate the beneficial effects of mTORC1/Stat3 modulation on regenerative tendon healing. The central hypothesis of the proposed research is that (i) injury-induced mTORC1 signaling governs fibrovascular scar formation during tendon healing, and (ii) Stat3 mediates mTORC1 function in fibrovascular scar formation via regulation of ECM organization. We will test the hypothesis using innovative multidisciplinary approaches, including mouse genetics, a surgical injury model, advanced molecular/imaging analyses, and a biomechanical test. The goal of Aim1 is to determine the function of mTORC1 in fibrovascular scar formation during tendon healing. The goal of Aim2 is to define Stat3 as a mediator of mTORC1 function in fibrovascular scar formation in tendons. The success of the proposed research will significantly advance the mechanistic understanding of fibrovascular scar formation during tendon healing and provide a new platform to develop translational and clinical researches targeting the mTORC1/Stat3 signaling cascade for the treatment of debilitating tendon diseases.


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 = $0 )
2026	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	12/4/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $346,775 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	5/15/2025	NON-COMPETING CONTINUATION	$25,025
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	11/26/2024	NON-COMPETING CONTINUATION	$321,750
														Subtotal = $346,775

Issue Date FY: 2024 ( Subtotal = $346,775 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	6/18/2024	NON-COMPETING CONTINUATION	$25,025
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	12/11/2023	NON-COMPETING CONTINUATION	$321,750
														Subtotal = $346,775

Issue Date FY: 2023 ( Subtotal = $357,500 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	11/16/2022	NON-COMPETING CONTINUATION	$321,750
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	2/16/2023	NON-COMPETING CONTINUATION	$35,750
														Subtotal = $357,500

Issue Date FY: 2022 ( Subtotal = $357,500 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	1/24/2022	NEW	$357,500
														Subtotal = $357,500

Grand Total All Awards = $1,408,550

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The function of mTORC1/Stat3 signaling in the regulation of fibrovascular scar formation during tendon healing

Award Number: R01AR079486

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: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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