(Verbatim from the Applicant): The long-term goal of our program is to define the molecular, cellular and physiological mechanisms that regulate osteoblast growth and differentiation, within the context of skeletal development and bone formation in vivo. Major contributions of this program to understanding bone cell biology and pathology include: (i) definition of distinct developmental stages and the principal transition points that together mediate establishment and maintenance of the osteoblast phenotype; (ii) characterization of molecular mechanisms that regulate cell growth regulatory genes, as well as induction and physiological responsiveness of bone-phenotypic genes during osteoblast growth and differentiation; and (iii) development of genetic models (e.g., using transgenic and gene knock-out mice) that provide the basis for bone tissue-specific gene therapy. Studies from this laboratory have contributed significantly to the discovery that Cbfa1 is a principal transcription factor controlling osteoblast differentiation and bone formation in vivo. We will continue to investigate the central role of Cbfa1 in mediating osteoblast growth and differentiation. We hypothesize that analysis of the physiological regulation of the bone-related Cbfa1 promoter will lead us to unidentified mechanisms that, together with BMP-2, control the onset and progression of osteogenesis. This hypothesis will be addressed experimentally by characterizing: (i) genomic occupancy of multiple elements in the Cbfa1 promoter by cognate regulatory factors in osseous cells; (ii) developmental regulation and physiological responsiveness of Cbfa1 gene transcription in vivo regulation of Cbfa1 expression; and (iv) BMP-2 inducible genes that function in conjunction with Cbfa1 to promote osteoblastic differentiation. Thus, the proposed studies will advance understanding of molecular, cellular and genetic mechanisms that initiate and support complete development of the osteoblast phenotype, as well as provide the basis for clinical strategies to treat a broad range of bone-related disorders.
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