Intercellular Signaling in Bone

缝隙连接蛋白43的突变或功能丧失会导致骨骼异常， 以成骨细胞基因缺失为特征的迟发性骨化和全身性成骨细胞功能障碍 转录和矿化潜力降低。我们之前已经将下行描述为 通过缝隙连接失去细胞间通讯所引起的基因转录调控是一种 细胞信号改变导致转录因子向启动子募集调节的结果 受影响的基因。需要评估的总体假设是，缝隙连接交流是 需要诱导细胞对细胞外信号的最佳反应来调节基因转录。这些 这些问题将在三个具体目标中得到解决：(1)分析缝隙连接在调节中的作用 响应细胞外信号调节成骨细胞功能的信号转导。(2)确定 允许缝隙连接信号转导的相互作用的分子基础。(3) 研究钙依赖信号在Cx43介导的基因转录中的作用。通过在上进行三角测量 缝隙结通道，由缝隙结传播的信使，以及由 在这些信号中，我们将大大阐述我们对缝隙连接功能的认识和理解 调节成骨细胞功能的背景。这些目标的实现将使用具有良好特点的 Cx43基因缺陷小鼠的成骨细胞系和原代成骨细胞。 意义：这些研究将提供对缝隙连接蛋白在细胞内的分子功能的洞察 细胞外信号的协调和传播，以及这些信号如何调节细胞功能 原子核的水平。我们的长期目标是开发预防和治疗骨骼疾病的方法 通过调节缝隙连接通讯增强生长的合成代谢反应的病理学 影响骨形成的因素。

The mutation or loss of function of the gap junction protein connexin43 leads to skeletal abnormalities, delayed ossification and a generalized osteoblast dysfunction, characterized by diminished osteoblast gene transcription and decreased mineralization potential. We have previously characterized that the down regulation of gene transcription caused by loss of intercellular communication through gap junctions is a result of altered cell signaling leading to regulation of the recruitment of transcription factors to the promoter of affected genes. The overall HYPOTHESIS to be evaluated is that gap junctional communication is required to elicit the optimal response of cells to extracellular cues to modulate gene transcription. These issues will be addressed in three SPECIFIC AIMS that will: (1) Analyze the role of gap junction in regulating signal transduction in response to extracellular signals to regulate osteoblast function. (2) Determine the molecular basis of interactions which permit signal transduction from the gap junction signaling nexus. (3) Examine the role of Ca2+-dependent signaling in Cx43-mediated gene transcription. By triangulating on the gap junction channel, the messenger propagated by the gap junction, and the signal cascades activated by these signals, we will greatly elaborate on our knowledge and understanding of gap junction function in the context of regulating osteoblast function. These aims will be carried out using well characterized osteoblastic cell lines and primary osteoblasts derived from Cx43 deficient mice. SIGNIFICANCE: The studies will provide insight into the molecular function of gap junction proteins in the coordination and propagation of extracellular signals and how these signals regulate cellular function at the level of the nucleus. Our long term goal is to develop methods for the prevention and treatment of skeletal pathologies by modulating gap junctional communication to potentiate the anabolic response of growth factors on bone formation.