Intercellular Signaling in Bone

骨中的细胞间信号传导

基本信息

批准号：
7385084
负责人：
Joseph P. Stains
金额：
$ 24.87万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
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/7385084
关键词：
Ablation Address Affect Animals Attenuated Biochemical COL1A1 gene Cell Line Cell Nucleus Cell physiology Cells Collagen Communication Complex Connexin 43 Connexins Cues Defect Detection Disease Docking Down-Regulation Exhibits FGF2 gene Fibroblast Growth Factor 2 Fluorescence Functional disorder Gap Junctions Gene Expression Genes Genetic Transcription Genetically Engineered Mouse Goals Growth Factor Hand Homeostasis IGF1 gene Image Analysis Immunofluorescence Immunologic Insulin-Like Growth Factor I Knockout Mice Knowledge Life Limb structure Mediating Methods Molecular Mus Mutation Nexus (resin cement)Numbers Osteoblasts Osteocalcin Osteocytes Osteogenesis Osteoporosis Pathology Prevention Rate Recruitment Activity Regulation Reporting Research Research Personnel Response Elements Role Serum Signal Transduction Signal Transduction Pathway Signaling Molecule Skeletal system Staining method Stains Testing Transactivation base bone bone cell craniofacial extracellular gap junction channel insight intercellular communication loss of function member mineralization mouse model mutant oculodentodigital dysplasia programs promoter protein protein interaction response transcription factor

项目摘要

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.

间隙连接蛋白connexin43的突变或功能丧失会导致骨骼异常，骨化延迟和普遍的成骨细胞功能障碍，其特征是成骨细胞基因减少转录和矿化潜力降低。我们之前已经描述过，向下由于间隙连接的细胞间通讯丧失而引起的基因转录调控是一种细胞信号传导改变导致转录因子募集到启动子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来调节基因转录。这些问题将在三个具体目标中得到解决，这些目标将：（1）分析间隙连接在调节中的作用响应细胞外信号的信号转导来调节成骨细胞功能。 (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。通过三角测量间隙连接通道、间隙连接传播的信使以及由间隙连接激活的信号级联这些信号，我们将极大地阐述我们对间隙连接功能的知识和理解调节成骨细胞功能的背景。这些目标将通过充分表征来实现来自 Cx43 缺陷小鼠的成骨细胞系和原代成骨细胞。意义：这些研究将深入了解缝隙连接蛋白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间隙连接通讯来增强生长的合成代谢反应来调节病理学影响骨形成的因素。