Funding

NIAMS Building Interdisciplinary Research Teams (BIRT) Awards Abstracts

Reviewed September 30, 2008

 

Principal Investigator: LOUIS J. SOSLOWSKY, Ph.D.

Grant: 3R01AR051000-03S1

Title: Rotator Cuff Tendon to Bone Insertion Site Healing

Institution: UNIVERSITY OF PENNSYLVANIA -- PA

Project Period: 2006/03/01-2011/02/28

DESCRIPTION (provided by applicant): The overall goal of this revision application is to build an interdisciplinary research team capable of developing and utilizing quantitative, non-invasive technologies for studies of soft tissue (tendon to bone) healing with a focus on the rotator cuff. The proposed team would combine an expert in the field of tendon and tendon to bone healing, Dr. Soslowsky, with experts in the field of nuclear magnetic resonance (NMR) with proficiency in tendon and bone, Dr. Navon and Dr. Wehrli respectively, to address important health problems. More specifically, Dr. Soslowsky is the PI on an active NIH/NIAMS R01 grant (the parent grant) comparing the efficacy of various post-operative activity levels on tendon to bone healing following surgical repair in a rotator cuff animal model. Dr. Navon has developed a NMR double-quantum-filtered (DQF) method for quantifying tendon structure, with which he has performed both animal and human studies. Dr. Wehrli has developed a magnetic-resonance (MR) technique (virtual bone biopsy) for quantifying trabecular bone structure, with which he has done multiple human studies. This team is therefore uniquely positioned to develop non-invasive techniques for quantifying tendon to bone healing in the rotator cuff, as well as to use these techniques to compare treatments (e.g., post-operative activity) making the team an ideal fit for the Funding Opportunity Announcement (AR-08-001: NIAMS Building Interdisciplinary Research Team (BIRT) Revision Awards). As stated above, the parent grant compares the efficacy of post-operative activity protocols on tendon to bone healing in a rotator cuff animal model. More specifically, we have previously shown that reducing the level of post-operative activity, by immobilization, resulted in improved biological, structural and mechanical properties of the repaired tendon to bone insertion site compared to either cage-activity or exercise [1, 2]. Importantly, the improvement in tissue structural properties, collagen organization, preceded the improvement in mechanical properties. Thus, collagen organization may be an early indicator of tendon to bone healing, a finding which forms a basic premise for this revision application. If collagen organization can ultimately be quantified in vivo, it could be used as a critical assay to determine when the insertion site has healed enough so as to benefit from remobilization. This would have tremendous scientific and clinical implications. Unfortunately, the only methods currently available to quantify collagen organization in our model require tissue excision at sacrifice, and are therefore not transferable clinically. This represents a significant barrier to future success in this area that can be removed through this interdisciplinary collaboration.

 

Grant: 3R01AR049921-06S1

Program Director: TYREE, BERNADETTE

Principal Investigator: WANG, JAMES H-C. Ph.D.

Title: Defining the role of tendon stem cells in the development of tendinopathy

Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH Pittsburgh , PA

Project Period: 2002/09/04-2011/08/31

DESCRIPTION (provided by applicant): While appropriate mechanical loading, such as exercise, is beneficial for maintaining tendon homeostasis, chronic, repetitive mechanical loading may lead to the development of tendinopathy, which is the leading cause of chronic disabilities that affects millions of people just in the United States alone. The typical histopathological features of tendinopathy have been identified, including accumulation of lipid cells, mucoid degeneration, and tissue calcification, either alone or in combination. These findings suggest the presence of cells with multi-phenotypes that differ from residential tenocytes, which express the fibroblast phenotype. During the course of investigation for our parent project, we have identified tendon stem cells, which constitute a sub-population of tendon cells and can undergo adipogenic, chondrogenic, and osteogenic differentiation. Therefore, we are now in good position to introduce stem cell biology into our investigation of the pathogenic mechanisms for the development of tendinopathy. Furthermore, accumulating evidence has pointed to the prominent role of adult stem cells in tissue pathologies, such as tumorigenesis. Thus, in this study, we aim to test a novel hypothesis that tendon stem cells play a major role in the development of tendinopathy by differentiating in "wrong" non-tenocyte directions (e.g., adipocytes, chondrocytes, and osteocytes) in response to chronic, repetitive mechanical loading placed on tendons. Therefore, the specific aim of this project is: To determine the effect of chronic, repetitive mechanical loading via treadmill running on the differentiation of mouse tendon stem cells (MTSCs) We will use histochemistry and immunohistochemistry to detect changes in the tendon matrix and cell phenotype in tendon sections. We will also extract tendon cells from tendon samples, characterize the differentiation state of MTSCs, and determine phenotypes of differentiated MTSCs (tenocytes and non- tenocytes) by gene and protein expression analysis (RT-PCR and Western blot), flow cytometry (i.e. FACS) analysis, and immunocytochemistry. Finally, we will use a novel biophysical approach, cell traction force microscopy (CTFM), to assess MTSC differentiation state and verify the results of biochemical analysis. This study is a logical extension of our parent project and is the first to investigate the role of tendon stem cells in the development of tendinopathy. The findings of this study will bring new insights into the precise pathogenesis of tendinopathy and may lead to the development of novel therapies for slowing down or reversing tendon degeneration, a hallmark of tendinopathy at later stages.