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Mechanisms of Skeletal Stem Cell Dysfunctions in Traumatic Bone Injuries

Award Number: R01AR072707
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: 07/12/2018
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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Mechanisms of Skeletal Stem Cell Dysfunctions in Traumatic Bone Injuries - Project Summary: Musculoskeletal diseases and disorders represent the second leading cause of disability and are a significant clinical burden worldwide. Among these disorders, musculoskeletal injuries can lead to complications in approximately 10% of the cases of bone fractures, and the risk of delayed- or non-union is increased up to 46% when associated with soft tissue and vascular injuries. While muscle is thought to play an important role in bone healing, the mechanisms of action remain poorly understood. There is a large knowledge gap in our understanding of muscle-bone crosstalk in regulating skeletal stem cell function in bone repair. We aim to elucidate the mechanisms by which muscle injury leads to impaired bone healing in a new muscle-bone injury model in mice that reflects traumatic injury in human. In this model, muscle crush injury severely impacts bone repair by delaying callus formation and stem cell recruitment. We have designed multiple experimental approaches, based on in vitro experiments, state-of-the-art genetic tools for lineage analyses and tissue grafting experiments in order to determine the extent to which traumatic injury in this model affects the coordinated activation and differentiation of skeletal stem cells in bone and adjacent muscle. Through these approaches, we will specifically identify the mechanisms of skeletal stem cell recruitment from muscle and periosteum in the fracture callus (aim 1), characterize the impaired skeletal stem cell activation in muscle and periosteum in the traumatic injury environment (aim 2) and the impact of traumatic injury on cartilage-to-bone transformation during bone regeneration (aim 3). Our work will help determine the causes of non-union associated with polytrauma and may lead to new drug- or cell-based therapies to treat traumatic musculoskeletal injuries and delayed bone healing.


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 = -$3,807 )
2024	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	7/29/2024	NON-COMPETING CONTINUATION	-$3,807
														Subtotal = -$3,807

Issue Date FY: 2022 ( Subtotal = $297,802 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	4/27/2022	NON-COMPETING CONTINUATION	$297,802
														Subtotal = $297,802

Issue Date FY: 2021 ( Subtotal = $291,784 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	4/26/2021	NON-COMPETING CONTINUATION	$291,784
														Subtotal = $291,784

Issue Date FY: 2020 ( Subtotal = $300,610 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	5/8/2020	NON-COMPETING CONTINUATION	$300,610
														Subtotal = $300,610

Issue Date FY: 2019 ( Subtotal = $299,528 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/25/2019	NON-COMPETING CONTINUATION	$299,528
														Subtotal = $299,528

Issue Date FY: 2018 ( Subtotal = $312,427 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/12/2018	NEW	$310,320
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	7/27/2018	NEW	$2,107
														Subtotal = $312,427

Grand Total All Awards = $1,498,344

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Mechanisms of Skeletal Stem Cell Dysfunctions in Traumatic Bone Injuries

Award Number: R01AR072707

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: 07/12/2018

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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