Skeletal development requires an exquisite coordination of programs for cell specification, migration, proliferation and differentiation that are regulated by interactions between tissue layers and the extracellular matrix. Many of the same events occur during adult bone repair. However, it is unclear to what extent the process of skeletal healing is a recapitulation of the skeletal development program. The goal of this research is to elucidate the molecular and cellular mechanisms regulating cranial skeletal repair, with a focus on the mandible. The underlying hypothesis is that adult tissues heal by using the fetal skeletogenic program. The following specific aims are propose. (1) Determine the spatial and temporal distribution of key chondrocyte- and osteoblast-specific gene products in the cranial skeleton by histological and molecular means. (2) Determine the mechanisms regulation repair in the mandible. In this aim, bones will be allowed to heal by primary intention (intramembranous ossification), and the expressions and functions of molecules that appear to regulate cranial skeletal tissues will be perturbed. (3) Determine the effects on cranial skeletal tissues of perturbing bone development by genetic and biochemical means. The gelatinase-B null mouse will be used to study the role of gelatinase B in regulation of mandibular bone formation. Gelatinase B mice have abnormal pattern of growth plate ossification due to a delay in angiogenesis. These experiments will assess similarities and differences between mandibular morphogenesis and long bone development. These studies may uncover fundamental differences between formation and repair of cranial skeletal tissues, or between the repair of cranial skeletal tissues and long bones. The long term goal is to use this information to develop biologically based therapies for the treatments of skeletal deformities and defects cause by trauma and disease.
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