Role of Cbfa1 Phosphorylation in Bone Metabolism

描述：（由申请人提供）Cbfal是区分所必需的 在骨形成的早期阶段， 阵它也是维持分化的成骨细胞所必需的。 细胞外基质合成通过一种途径刺激Cbfal活性 涉及MAP激酶和Cbfal磷酸化。MAP激酶依赖性Cbfal 磷酸化可能在骨形成的调节中起重要作用 和再生。我们的长期目标是了解Cbfal磷酸化 受已知影响骨生成的信号调节， Cbfal磷酸化与骨形成和再生之间的关系。我们以前的 研究导致了以下两个假设的发展，将在 本项目： 1.骨生长因子和细胞因子，包括BMP-2、TGF-β 1、IGF-1、FGF-I和TGF-β 2。 2、PDGF-BB和IL-6调节MAP途径和Cbfal磷酸化。cbfal 磷酸化对于转录的激活和转录的调节是必需的。 成骨细胞增殖、分化和骨形成。2.机械 负载刺激MAP激酶途径和Cbfal磷酸化，因此， 增加成骨细胞活性和骨形成。 这些假设将通过实现以下目标来解决 具体目标：1.测定包括BMP-2、TGF-β 1、IGF-1、FGF-1 和2，PDGF-BB和IL-6对MAPK和Cbfal磷酸化水平的影响;将这些 成骨细胞增殖和分化的变化。2.确定 机械负荷对MAPK和Cbfal磷酸化水平的影响 如对成骨细胞增殖和分化的影响。 这些研究将提供有用的基本新知识， 骨生长因子促进骨形成和再生的分子机制 和细胞因子以及通过机械负荷。

DESCRIPTION: (provided by applicant) Cbfal is essential for the differentiation of osteoblasts from mesenchymal precursors, during early stages of bone formation. It is also required for maintenance of differentiated osteoblasts. Extracellular matrix synthesis stimulates Cbfal activity through a pathway involving MAP kinase and Cbfal phosphorylation. MAP kinase-dependent Cbfal phosphorylation may play an important role in the regulation of bone formation and regeneration. Our long-term goal is to understand how Cbfal phosphorylation is regulated by signals known to affect osteogenesis and the relationship between Cbfal phosphorylation and bone formation and regeneration. Our previous study led to the development of the following two hypotheses that will be in this project: 1. Bone growth factors and cytokines including BMP-2, TGF-bl, IGF-1, FG F-1 and 2, PDGF-BB, and IL-6 regulate MAP pathways and Cbfal phosphorylation. Cbfal phosphorylation is essential for activation of transcription and regulation of osteoblastic proliferation, differentiation and bone formation. 2. Mechanical loading stimulates MAP kinase pathways and Cbfal phosphorylation, thus, increase osteoblastic activity and bone formation. These hypotheses will be addressed through achievement of the following specific aims: 1. Determine the effects including BMP-2, TGF-bl, IGF-1, FGF-1 and 2, PDGF-BB, and IL-6 on MAPK and Cbfal phosphorylation levels; relate these changes to osteoblastic proliferation and differentiation. 2. Determine the effects of mechanical loading on MAPK and Cbfal phosphorylation levels as well as on osteoblastic proliferation and differentiation. These studies will provide useful fundamental new knowledge regarding the molecular mechanism of bone formation and regeneration by bone growth factors and cytokines as well as by mechanical loading.