Tuesday, January 13, 2026 1/13/2026

Extracellular Matrix Regulation of Inflammatory Signaling in Tendon

Award Number: R01AR083343
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: 04/05/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Extracellular Matrix Regulation of Inflammatory Signaling in Tendon - Abstract Twenty percent of all primary care consults are related to musculoskeletal diseases; 30% of these are associated with tendinopathies. Pathogenesis of tendinopathy includes increased inflammatory signaling and extracellular matrix (ECM) remodeling. This remodeling leads to softer tendinopathic tendons, increasing the risk of tearing. Yet the relative roles of chronic inflammation and ECM stiffness in the initiation and progression of tendon disease remain controversial and are difficult to decouple in patient populations. We and others have shown that, in 2D cell culture using interleukin-1β (IL-1β) as a stimulant, patient-derived tendinopathic fibroblasts exhibit a stronger inflammatory response that is further enhanced on soft substrates. This inflammatory response is dependent on NF-κB signaling, which we have previously established as a critical regulator of tendon disease and healing. Yet these studies are limited by the use of classical 2D culture approaches and fail to recapitulate in vivo cell behavior or provide insight into ECM remodeling. The ability to visualize cytokine receptor clustering in 3D environments has further demonstrated that cellular sensitivity to cytokines is based on the properties of the ECM. Although these studies suggest physicochemical coupling between ECM stiffness (physical) and inflammatory signaling (chemical) that sustains chronic loss of tendon mechanical function, the mechanisms of how ECM drives cell behavior in 3D tissues like tendon remain unknown. Therefore, there remains a critical need to define the physicochemical cell-ECM interactions that regulate tendon function to discover the mechanisms underlying tendinopathies and treatments. Our long-term goal is to develop therapeutic strategies for the clinical treatment of tendinopathy by identifying key cell-ECM mechanisms driving chronic inflammatory tendon disease. Our overall objective in this application is to develop a novel approach to studying the physicochemical coupling between ECM stiffness and inflammatory signaling by developing a tendon specific microphysiological system (MPS) with tunable stiffness. In Aim 1 we will establish a tendon specific MPS with tunable ECM stiffness that quantifies mechanical function in situ. We will quantify tendon function by measuring micro-cantilever displacement in situ and tune ECM stiffness using light- induced matrix polymerization. In Aim 2 we will demonstrate that inflammatory signaling in primary human tendon fibroblasts is modulated by ECM stiffness via inflammatory receptor clustering. In Aim 3 we will evaluate if and how pathogenic tendon fibroblast phenotype is regulated by ECM stiffness. At the completion of this proposed work, our expected outcomes are to develop an MPS relevant to tendon function and deliver new insight into tendon cell-ECM interactions that govern tendon pathogenesis. These results will have a positive impact by providing the field with a repeatable and tunable platform to improve our understanding of tendon pathology, ultimately leading to new opportunities for the development of novel 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: 2026 ( Subtotal = $308,880 )
2026	2026	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	1/6/2026	NON-COMPETING CONTINUATION	$308,880
														Subtotal = $308,880

Issue Date FY: 2025 ( Subtotal = $332,904 )
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	2	5/15/2025	NON-COMPETING CONTINUATION	$24,024
2025	2025	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	1/22/2025	NON-COMPETING CONTINUATION	$308,880
														Subtotal = $332,904

Issue Date FY: 2024 ( Subtotal = $343,200 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	4/5/2024	NEW	$343,200
														Subtotal = $343,200

Grand Total All Awards = $984,984

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Extracellular Matrix Regulation of Inflammatory Signaling in Tendon

Award Number: R01AR083343

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: 04/05/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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