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Mechanisms underlying tendon regeneration and attachment site pattern restoration

Award Number: R01AR074541
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: 12/01/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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Mechanisms underlying tendon regeneration and attachment site pattern restoration - Galloway, Jenna L Project Summary Tendons make essential connections between the forming musculoskeletal tissues, enabling coordinated movement. Disruption to the development and patterning of the musculoskeletal system can result in skeletal malformations or contractures, a congenital abnormality that results in constriction in the movement of joints. In adults, musculoskeletal injuries are common among active individuals and the aging population. Tendon injuries, in particular, are complicated by a slow and limited healing, which can pose significant mobility, pain, and quality of life issues. Comprehensive knowledge of the molecular pathways that guide tendon development and regeneration would have broad impact in our understanding of the etiology of congenital defects as well as in regenerative medicine approaches to tendon injuries. This proposal aims to use the zebrafish to understand the mechanisms underlying tendon cell regeneration and the re-establishment of attachment site pattern. Our previous studies have shown that zebrafish and mammalian tendons are similar in gene expression, developmental regulation, and ultrastructural properties, making them an excellent genetic system for studying tendon biology. We also find zebrafish have robust abilities to regenerate their tendon tissue unlike adult mammals. Building from this novel work, we propose to use a genetic cell ablation model to dissect the cellular and molecular mechanisms underlying tendon regeneration and the restoration of the attachment pattern. We will identify the source of the newly regenerating tendon cells using cell proliferation assays, genetic lineage tracing, and live imaging. Examination of BMP Responsive Element transgenic zebrafish and functional analysis indicate BMP signaling in the regeneration of specific attachment sites. In addition, a high-throughput chemical screen identified compounds with tendon promoting activities and whose targets may intersect the BMP pathway. Using chemical and genetic functional assays, we will dissect the role of BMP signaling in tendon regeneration and the re-establishment of a specific attachment site. We will also test if the chemicals and the pathways they target can augment the regenerative response through their potential intersection with the BMP pathway. Our proposal combines novel tools with live imaging and functional studies and together, this will provide unprecedented visualization of tendon cell behaviors during regeneration. We believe these studies will add crucial insight into tendon development and regeneration, which could impact our understanding of congenital disorders and regenerative medicine approaches to tendon injuries.


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 = $0 )
2024	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	4/9/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $369,600 )
2023	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	4/24/2023	NON-COMPETING CONTINUATION	$36,960
2023	2023	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	11/11/2022	NON-COMPETING CONTINUATION	$332,640
														Subtotal = $369,600

Issue Date FY: 2022 ( Subtotal = $365,904 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	5/30/2022	NON-COMPETING CONTINUATION	$33,264
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	11/29/2021	NON-COMPETING CONTINUATION	$332,640
														Subtotal = $365,904

Issue Date FY: 2021 ( Subtotal = $358,512 )
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	1/5/2021	NON-COMPETING CONTINUATION	$332,640
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	5/18/2021	NON-COMPETING CONTINUATION	$25,872
														Subtotal = $358,512

Issue Date FY: 2020 ( Subtotal = $369,600 )
2020	2020	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	4/23/2020	NON-COMPETING CONTINUATION	$36,960
2020	2020	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	11/22/2019	NON-COMPETING CONTINUATION	$332,640
														Subtotal = $369,600

Issue Date FY: 2019 ( Subtotal = $369,600 )
2019	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	11/19/2018	NEW	$369,600
														Subtotal = $369,600

Grand Total All Awards = $1,833,216

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Mechanisms underlying tendon regeneration and attachment site pattern restoration

Award Number: R01AR074541

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: 12/01/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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