contributed considerably to the characterization of the differentiating fetal rat calvaria cell system, in terms of the biochemical, morphological and gene regulatory parameters that characterize osteoblast development. Concepts and experimental approaches developed during the past funding period will now be pursued to address regulatory mechanisms that control osteoblast proliferation and differentiation. The applicants' current working hypothesis is that the progressive development of the osteoblast phenotype is controlled by the expression and activities of key regulatory factors; that regulatory factors in proliferating osteoblasts have consequential effects on both growth control, and post-proliferative events; and that regulatory factors expressed in differentiating osteoblasts are selectively utilized to suppress growth and to support expression of genes for development of bone tissue. The first Specific Aim will examine cyclins, cyclin-dependent kinases, and inhibitors, with a focus on cyclin B and E, which were shown to be up-regulated postproliferatively during osteoblast phenotype development. The second Specific Aim will examine the AP-1 transcription factors, focusing on fra2 and junD, which have been shown to have roles in osteoblast development.
Specific Aim 3 will focus on the AML-1 runt homology (pattern formation) protein, which has been shown to be important for bone tissue-specific transcription. Functional activities of these factors will be determined by selectively altering the timing and/or levels of these factors by overexpression, or by antisense and dominate-negative strategies and then determining whether the development of the osteoblast phenotype is modified. The applicants suggest that by defining mechanisms contributing to the control of osteoblast growth and differentiation, they will provide new avenues for targeted therapeutic approaches to disorders of bone formation.
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