Intercellular Signaling in Bone

骨中的细胞间信号传导

• 批准号: 7096721
• 负责人: Joseph P. Stains
• 金额: $ 26.14万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096721
• 关键词: biological signal transduction; calcium channel; calcium flux; cell line; fibroblast growth factor; fluorescence microscopy; gap junctions; genetic regulation; genetic transcription; genetically modified animals; insulinlike growth factor; laboratory mouse; membrane channels; normal ossification; osteoblasts; osteocytes; polymerase chain reaction; protein protein interaction; skeletal disorder; transcription factor

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：间隙连接蛋白 connexin43 的突变或功能丧失会导致骨骼异常、骨化延迟和全身成骨细胞功能障碍，其特征是成骨细胞基因转录减少和矿化潜力降低。我们之前已经研究过，由于细胞间间隙连接通讯丧失而引起的基因转录下调是细胞信号传导改变的结果，导致转录因子募集到受影响基因启动子的调节。要评估的总体假设是，需要间隙连接通讯来引发细胞对细胞外信号的最佳反应，以调节基因转录。这些问题将在三个具体目标中得到解决，这些目标将：（1）分析间隙连接在响应细胞外信号调节信号转导以调节成骨细胞功能中的作用。 (2)确定允许从间隙连接信号传导连接进行信号转导的相互作用的分子基础。 (3) 检查Ca2+依赖性信号传导在Cx43介导的基因转录中的作用。通过对间隙连接通道、间隙连接传播的信使以及这些信号激活的信号级联进行三角测量，我们将在调节成骨细胞功能的背景下详细阐述我们对间隙连接功能的知识和理解。这些目标将使用来自 Cx43 缺陷小鼠的特征明确的成骨细胞系和原代成骨细胞来实现。意义：这些研究将深入了解间隙连接蛋白在细胞外信号协调和传播中的分子功能，以及这些信号如何在细胞核水平调节细胞功能。我们的长期目标是通过调节间隙连接通讯来开发预防和治疗骨骼病理学的方法，以增强生长因子对骨形成的合成代谢反应。