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Impacts of mechanosensation and matrix architecture on cell fate specification in traumatic heterotopic ossification

Award Number: R01AR078324
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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Impacts of mechanosensation and matrix architecture on cell fate specification in traumatic heterotopic ossification - Project Summary Heterotopic ossification (HO) is the pathologic formation of extra-skeletal bone forming almost exclusively at sites of mechanical stress, that occurs in ~20% of patients after hip arthroplasty, burns or musculoskeletal injury. Currently, no therapeutics or physical therapy-based protocols exist to prevent HO. In this regard, there is a void in our understanding of the causative mechanotransductive pathways behind this debilitating process. Our unbiased transcription profiles in mouse HO-mesenchymal progenitor cells (MPCs) recovered from HO sites in combination with immunostaining of mouse and human HO revealed that a series of mechanotranduction-linked pathways, including discoidin receptor 2 (DDR2), FAK and the Hippo effectors, YAP and TAZ, are highly upregulated in tandem with observed changes in extracellular matrix (ECM) alignment. Using a novel, regional MPC-specific inducible Cre system (Hoxa11-CreERT2), we have compiled preliminary data that support critical roles for DDR2 signaling and stage-specific immobilization in both triggering FAK/YAP/TAZ signaling and MPC lineage commitment, but also an unexpected function in controlling ECM alignment. Together, these observations have led to our central hypothesis that MPC DDR2 signaling is necessary for mobility-induced changes in ECM alignment that trigger aberrant osteochondral differentiation at HO sites and can be blocked by DDR2 inhibition or injury stage-specific immobilization. Aim 1: Define the role of DDR2 as a critical upstream regulator of FAK/YAP/TAZ signaling in controlling the induction and progression of HO. We hypothesize that DDR2-mechanotransductive signaling alters osteochondral differentiation and HO in vivo and can be targeted with cell specific deletion models or translatable clinical therapies. Aim 2: Determine the optimal post-injury timing during which MPCs can be redirected away from aberrant osteochondral fate and pathologic ECM alignment through immobilization-based intervention. We hypothesize that immobilization during the early proliferative phase after injury will block pathologic changes in ECM alignment with disease-ameliorating effects on MPC fate determination and aberrant ossification. Aim 3: Characterize the role of mobilization-induced DDR2 activation on collagen alignment/anisotropy and mechanotransductive signaling. We hypothesize that DDR2 activity drives ECM alignment independently of limb mobility in vivo or cyclic stretch in vitro. Impact: The proposed studies will provide a comprehensive and mechanistic understanding of how DDR2 and joint mobility regulate ECM alignment, cell fate and HO using conditional deletion models and clinical therapies.


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 = $386,653 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	5	4/17/2025	NON-COMPETING CONTINUATION	$398,253
2025	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	3/14/2025	SUPPLEMENT FOR EXPANSION	-$11,600
														Subtotal = $386,653

Issue Date FY: 2024 ( Subtotal = $452,616 )
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	5/6/2024	SUPPLEMENT FOR EXPANSION	$11,600
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	002	4	6/6/2024	NON-COMPETING CONTINUATION	$31,825
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	5/3/2024	NON-COMPETING CONTINUATION	$409,191
														Subtotal = $452,616

Issue Date FY: 2023 ( Subtotal = $572,576 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	3	6/15/2023	SUPPLEMENT FOR EXPANSION	$139,195
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	6/9/2023	NON-COMPETING CONTINUATION	$433,381
														Subtotal = $572,576

Issue Date FY: 2022 ( Subtotal = $562,713 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	6/6/2022	SUPPLEMENT FOR EXPANSION	$127,595
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	4/25/2022	NON-COMPETING CONTINUATION	$435,118
														Subtotal = $562,713

Issue Date FY: 2021 ( Subtotal = $428,360 )
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/9/2021	NEW	$428,360
														Subtotal = $428,360

Grand Total All Awards = $2,402,918

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Impacts of mechanosensation and matrix architecture on cell fate specification in traumatic heterotopic ossification

Award Number: R01AR078324

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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