Intercellular Signaling in Bone

差距连接蛋白连接蛋白43的突变或功能丧失导致骨骼异常， 延迟骨化和普遍的成骨细胞功能障碍，特征为成骨细胞基因减少 转录和降低矿化潜力。我们之前已经描述过， 通过间隙连接的细胞间通讯的丧失引起的基因转录的调节是一种 细胞信号传导改变导致转录因子向启动子募集的调节的结果 受影响的基因。要评估的总体假设是，间隙连接通讯是 需要引起细胞对细胞外信号的最佳反应以调节基因转录。这些 本文将从以下三个方面来探讨这一问题：（1）分析缝隙连接在调节细胞凋亡中的作用， 信号转导应答细胞外信号以调节成骨细胞功能。(2)确定 允许信号从差距连接信号联系传递的相互作用的分子基础。（三） 研究Ca2+依赖性信号在Cx43介导的基因转录中的作用。通过三角测量 缝隙连接通道，由差距连接传播的信使，以及由缝隙连接激活的信号级联。 这些信号，我们将大大阐述我们的知识和理解的间隙连接功能， 调节成骨细胞功能的背景。这些目标将使用具有良好特征的 成骨细胞系和来源于Cx43缺陷小鼠的原代成骨细胞。 意义：这些研究将提供深入了解间隙连接蛋白在细胞内的分子功能。 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， 核的水平。我们的长期目标是开发预防和治疗骨关节炎的方法。 通过调节间隙连接通讯以增强生长的合成代谢反应 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.