Our purpose is to gain a greater understanding of the basic cellular and molecular mechanisms that lead to tendinopathies and to translate these studies to the clinic. Tendon diseases can be painful, debilitating and significantly detract from the quality of one's life. Much of what we know about tendon fibroblast cell biology comes from in vitro cell culture studies or descriptive histological studies of diseased and healthy tissue. There has been a lack of in vivo, mechanism driven studies that combine contemporary molecular biology and genetics with precise tissue mechanics and functional measures. The long-term goal of this project is to better understand tendon fibroblast biology in the context of injury and disease, and to improve the treatment of tendinopathies. For many tissues in the body, the genes that control embryonic tissue development are also important in the repair and regeneration of adult tissues. Scleraxis is a bHLH transcription factor that is critical for the embryonic development of limb tendons, but little is known about scleraxis function in adult tendons. Our overall hypotheses are that scleraxis is important for the adaptation of tendons to mechanical loading, scleraxis is regulated by TGF-? and IGF-1 signaling pathways, and that dysregulation of scleraxis is a central factor in the development of tendinosis. These hypotheses are rigorously tested in three Specific Aims that use a multidisciplinary approach involving a combination of molecular biology and tissue mechanics experiments in adult wild type mice (ScxWT), adult transgenic mice with a postnatal inducible knockdown of scleraxis (ScxKD), and in cultured primary tendon fibroblast cells from humans and mice. These studies will provide important insight into adult tendon fibroblast physiology, and lay the groundwork for future translational studies focused on scleraxis to improve the treatment of patients suffering from tendinopathies.

Public Health Relevance

to public health is based upon the tremendous impact that tendon injuries and diseases have on mobility and quality of life. There is a substantial lack in our understanding of how tendons adapt to new stresses placed upon them, and how tendons recover from injuries. Increasing our understanding of fundamental adult tendon biology and translating this to patients is highly relevant to the NIH's mission to reduce the burdens of human disability.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR063649-02
Application #
8706801
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Tyree, Bernadette
Project Start
2013-08-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Orthopedics
Type
Schools of Medicine
DUNS #
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Gumucio, Jonathan P; Flood, Michael D; Roche, Stuart M et al. (2016) Stromal vascular stem cell treatment decreases muscle fibrosis following chronic rotator cuff tear. Int Orthop 40:759-64
Mendias, Christopher L; Schwartz, Andrew J; Grekin, Jeremy A et al. (2016) Changes in muscle fiber contractility and extracellular matrix production during skeletal muscle hypertrophy. J Appl Physiol (1985) :jap.00719.2016
Wilde, Jeffrey M; Gumucio, Jonathan P; Grekin, Jeremy A et al. (2016) Inhibition of p38 mitogen-activated protein kinase signaling reduces fibrosis and lipid accumulation after rotator cuff repair. J Shoulder Elbow Surg 25:1501-8
Dueweke, Jeffrey J; Awan, Tariq M; Mendias, Christopher L (2016) Regeneration of Skeletal Muscle Following Eccentric Injury. J Sport Rehabil :1-24
Garcia, Stefan C; Dueweke, Jeffrey J; Mendias, Christopher L (2016) Optimal Joint Positions for Manual Isometric Muscle Testing. J Sport Rehabil :1-13
Hudgens, Joshua L; Sugg, Kristoffer B; Grekin, Jeremy A et al. (2016) Platelet-Rich Plasma Activates Proinflammatory Signaling Pathways and Induces Oxidative Stress in Tendon Fibroblasts. Am J Sports Med 44:1931-40
Russell, Katelyn A; Ng, Rainer; Faulkner, John A et al. (2015) Mouse forepaw lumbrical muscles are resistant to age-related declines in force production. Exp Gerontol 65:42-5
Davis, Max E; Korn, Michael A; Gumucio, Jonathan P et al. (2015) Simvastatin reduces fibrosis and protects against muscle weakness after massive rotator cuff tear. J Shoulder Elbow Surg 24:280-7
Roche, Stuart M; Gumucio, Jonathan P; Brooks, Susan V et al. (2015) Measurement of Maximum Isometric Force Generated by Permeabilized Skeletal Muscle Fibers. J Vis Exp :e52695
Schwartz, Andrew J; Sarver, Dylan C; Sugg, Kristoffer B et al. (2015) p38 MAPK signaling in postnatal tendon growth and remodeling. PLoS One 10:e0120044

Showing the most recent 10 out of 17 publications