The objective of this proposal is to provide the applicant with exemplary research training in skeletal biology. To achieve this objective, a training regimen focused upon synovial joint morphogenesis has been developed, consisting of research aims and substantial training activities. Synovial joints are essential for skeletal function and quality of life and much is known about their anatomical organization, distinct tissues and susceptibility to common pathologies including age-dependent osteoarthritis. In contrast, very little is known about their developmental biology. Were such information available, it could be used directly or in combination with bioengineering tools to create new joint repair and regenerative strategies such as engineered stem cells with specific joint tissue-formation capacity; these strategies could counter the notoriously poor intrinsic repair capacity of joint tissues. Our central hypothesis for this work is that the early population of multipotent mesenchymal interzone cells at incipient joint sites in the embryonic limb is topographically modulated by the retinoid and Wnt/-Catenin signaling pathways to permit formation of distinct joint tissues over time.
Our aims for this fellowship research project are (1) to characterize the roles of retinoid signaling and its interaction with Wnt/-Catenin to regulate interzone cell function and joint tissue formation and (2) to determine interzone cell plasticity and differentiation capacity during joint development as well as in repair of mature joint tissues in postnatal animals. The project outlined in the proposal combines work of fundamental basic research importance with work directed toward the future creation of novel cell-, pharmacologic- or gene-based therapies for joint disease in the affected or elderly population. Overall, the project represents a balanced and effective training regimen to allow the applicant to fully develop the technical and intellectual skills needed to establish a successful and independent research program in the future.

Public Health Relevance

Skeletal development and growth are fundamental processes that when defective, can cause major pathologies in the craniofacial, trunk and limb skeleton and can lead to impairment of body function and quality of life. The goal of this proposal is to develop an understanding of mechanisms which direct synovial joint morphogenesis. The project will provide novel insights into developmental mechanisms which may also have significant relevance for translational medicine and creation of future novel and specifically engineered cell-based strategies for repair, regeneration and reconstruction of affected joints.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32AR064071-03
Application #
8846476
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Tyree, Bernadette
Project Start
2013-07-01
Project End
2016-06-30
Budget Start
2015-07-01
Budget End
2016-06-30
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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Bechtold, Till E; Saunders, Cheri; Decker, Rebekah S et al. (2016) Osteophyte formation and matrix mineralization in a TMJ osteoarthritis mouse model are associated with ectopic hedgehog signaling. Matrix Biol 52-54:339-354
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Decker, Rebekah S; Koyama, Eiki; Pacifici, Maurizio (2015) Articular Cartilage: Structural and Developmental Intricacies and Questions. Curr Osteoporos Rep 13:407-14
Ishizuka, Y; Shibukawa, Y; Nagayama, M et al. (2014) TMJ degeneration in SAMP8 mice is accompanied by deranged Ihh signaling. J Dent Res 93:281-7
Decker, Rebekah S; Koyama, Eiki; Enomoto-Iwamoto, Motomi et al. (2014) Mouse limb skeletal growth and synovial joint development are coordinately enhanced by Kartogenin. Dev Biol 395:255-67
Decker, Rebekah S; Koyama, Eiki; Pacifici, Maurizio (2014) Genesis and morphogenesis of limb synovial joints and articular cartilage. Matrix Biol 39:5-10