Intercellular Signaling in Bone

骨中的细胞间信号传导

• 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
• 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

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，