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Tendon Tissue Engineering Informed by Lysyl Oxidase Regulation of Embryonic Tendon Mechanical Properties

Award Number: R01AR072886
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Musculoskeletal injuries are a leading cause of disability and medical costs in the United States. Approximately half of these injuries involve tendons and ligaments. The lifelong dysfunction, pain, and increased risk of re- injury due to poor healing have motivated our long-term goal to regenerate new tendon from stem cells to restore function and quality of life. Typical stem cell-based approaches aim to promote quantity of extracellular matrix (ECM) content, with the assumption that ECM quantity correlates with mechanical properties. However, these approaches have yet to achieve functional tendons. This has led us to ask how tendon develops naturally in the embryo to inform a mesenchymal stem cell (MSC)-based tendon regeneration approach. Our studies in the chick embryo recently showed that lysyl oxidase (LOX)-mediated crosslinking correlates strongly with mechanical properties during tendon development, and that inhibition of LOX activity reduces crosslinking and elastic modulus despite continued increases in matrix content. Furthermore, LOX activity appears to be regulated by embryonic kicking (mechanical loading). Based on these exciting data, we hypothesize LOX is a critical regulator of developing tendon mechanical properties, and that developmentally informed manipulation of LOX activity can promote functional tendon regeneration with MSC. The hypothesis will be tested with the following three specific aims: 1) determine LOX expression patterns and role in embryonic tendon mechanical property development; 2) elucidate how mechanical loading regulates LOX during embryonic tendon development; 3) develop approaches to enhance engineered MSC-construct mechanical properties via LOX-mediated crosslinking. The proposed work is innovative because our approach focuses on restoring ECM quality, rather than quantity, of the regenerating tendon matrix, and aims to inform this approach with embryonic development. Our novel strategy combines the chick embryo model with tissue engineering and bioreactor loading systems to investigate LOX and mechanical loading interactions in functional tendon development. Our long-term goal is to design developmentally inspired LOX-targeted therapies utilizing MSC to improve tendon mechanical properties.


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 = $0 )
2025	2021	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	11/21/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	7/10/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2019	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	1/20/2022	NON-COMPETING CONTINUATION	-$194,271
2022	2019	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	4	1/20/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$314,057
2022	2018	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	1/20/2022	NON-COMPETING CONTINUATION	-$119,786
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $267,608 )
2021	2021	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	5	9/6/2021	NON-COMPETING CONTINUATION	$319,996
2021	2019	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	8/17/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$138,341
2021	2019	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	8/17/2021	NON-COMPETING CONTINUATION	-$190,729
														Subtotal = $267,608

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	9/8/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $385,000 )
2019	2019	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	9/11/2019	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2018 ( Subtotal = $385,000 )
2018	2018	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	8/27/2018	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2017 ( Subtotal = $382,300 )
2017	2017	UNIVERSITY OF ROCHESTER	500 JOSEPH C WILSON BLVD	ROCHESTER	NY	14627	MONROE	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	9/21/2017	NEW	$382,300
														Subtotal = $382,300

Grand Total All Awards = $1,419,908

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Tendon Tissue Engineering Informed by Lysyl Oxidase Regulation of Embryonic Tendon Mechanical Properties

Award Number: R01AR072886

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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