Craniofacial skeletal muscle defects occur in certain myopathies, such as muscular dystrophy; in congenital deformities, such as hemifacial microsomia and facial/palatal clefts; and as a result of surgical procedures for oral cancer or trauma. Success in the repair or replacement of muscle defects is limited by difficulty in transplantation and survival of muscle tissue. An important structure of muscle is the myotendinous junction (MTJ), which transduces force generated by muscle to its connective tissue attachment site. How this complex structure is formed in developing muscle or repaired after injury or disease is poorly understood. Attachment of the muscle fiber to the connective tissue appears to involve adhesion receptors, including the alpha7-beta1 integrin. In addition, during muscle development and repair, alpha7 integrin seems important for myoblast adhesion and motility. The long- term objective of the proposed studies is to further define the molecular mechanisms by which the laminin-binding alpha7 integrin organizes the MTJ in developing and regenerating skeletal muscle. The hypothesis is that the alternatively spliced isoforms of alpha7 not only regulate transient adhesion during myoblast motility but also form the long-lived MTJ.
The specific aims are 1) to determine the expression levels and distribution of laminin-binding integrins during skeletal muscle development, 2) to analyze the functionality of alpha7,beta1 alternatively spliced isoforms, and 3) to determine the role of the alternatively spliced extracellular domain in regulating alpha7 activation. The experimental approach is first to define the developmentally complex expression patterns of the alpha7 splice variants and their ligands. Next, alpha7 isoforms will be analyzed for their role in cell motility and assembly of MTJ-like structures. Finally, the role of the extracellular domain splice variants in regulating alpha7 activity will be addressed using molecular approaches. These studies will enhance understanding of the structure and assembly of the MTJ and suggest new approaches in tissue engineering to promote reconstruction of craniofacial skeletal muscle defects caused by disease, trauma, or surgical procedures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013479-03
Application #
6350614
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Kousvelari, Eleni
Project Start
1999-02-01
Project End
2004-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
3
Fiscal Year
2001
Total Cost
$204,540
Indirect Cost
Name
University of California San Francisco
Department
Anatomy/Cell Biology
Type
Schools of Dentistry
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Ziober, B L; Chen, Y Q; Ramos, D M et al. (1999) Expression of the alpha7beta1 laminin receptor suppresses melanoma growth and metastatic potential. Cell Growth Differ 10:479-90