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Role of Ephrins in Osteoblast Differentiation

Ephrins 在成骨细胞分化中的作用

基本信息

批准号：
8073546
负责人：
M. Douglas Benson
金额：
$ 10.99万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-17 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8073546
关键词：
Actins Address Adult Age Alkaline Phosphatase Area Basic Science Binding Sites Biological Assay Biology Bone Diseases Bone Growth Bone Tissue Brain Calvaria Cells Cephalic Characteristics Cleidocranial Dysplasia Clinical Clinical Treatment Collagen Collagen Fibril Congenital Abnormality Craniosynostosis Cytoskeleton Data Defect Deformity Development Developmental Biology Disease Elderly Elements Eph Family Receptors EphB4 Receptor Ephrin-B2 Ephrins Equilibrium Event Extracellular Domain Extracellular Matrix Failure Foundations Future Gene Activation Gene Expression Gene Expression Regulation Generations Genes Genetic Transcription Goals Growth Growth Factor Integrins Knowledge Lead Life Ligand Binding Ligands Literature Luciferases Measures Mediating Membrane Methods Minerals Mitogen-Activated Protein Kinases Modeling Molecular Molecular Biology Morphology Motivation Mus Occupations Organ Culture Techniques Organogenesis Osteoblasts Osteocalcin Osteogenesis Osteoporosis Parietal Pathogenesis Pathway interactions Patients Phosphorylation Positioning Attribute Process Production Protein Secretion Protein Tyrosine Kinase Proteins Public Health Publishing Reagent Recombinants Regulation Reporter Role Set protein Signal Transduction Signal Transduction Pathway Site Staging Surgical sutures System Thick Tissues Transgenic Organisms Width Wild Type Mouse Work axon guidance base bone bone metabolism bone sialoprotein cell motility cis acting element clinically relevant cranium defined contribution density effective therapy experience homeodomain in vivo innovation long bone member new therapeutic target novel osteoblast differentiation osteopontin osteoporosis with pathological fracture overexpression promoter public health relevance receptor research study skeletal transcription factor

项目摘要

DESCRIPTION (provided by applicant): Skeletal viability requires precise regulation of bone synthesis throughout life, and the catastrophic pathological conditions that accompany its failure present a major public health challenge. Nevertheless, the mechanisms through which synthesis of bone is regulated by signals from the surrounding tissues are not understood, and this lack of knowledge hampers the ability to treat diseases of defective bone growth. The long-term goal of this group is therefore to understand the molecular mechanisms that control differentiation of the osteoblast (OB), the bone-forming cell, so as to better manipulate bone synthesis in the treatment of bone diseases. Recent work in the literature and preliminary data presented herein suggest and support a central role for the contact-mediated promotion of OB differentiation by members of the Eph family of receptor tyrosine kinases and their ligands, the ephrins. Specifically:1) Ephs and ephrins are expressed in discrete layers of osteogenesis in vivo, and 2) treatment of OBs with soluble recombinant ephrin increases OB-specific gene expression and bone synthesis. Based on this evidence, this proposal advances the central hypothesis that Eph signaling regulates bone growth through the activation of specific osteoblast gene promoter elements. The rationale for the proposed studies is that a deeper understanding of how these receptors participate in contact-mediated OB differentiation will reveal control points for exploitation in future therapies. This hypothesis will be addressed through completion of two specific aims:1) Determine the effect of activating or blocking Eph signaling on normal and defective bone formation, and 2) Define the contribution of specific promoter elements to OB gene activation. Studies under the first aim will apply recombinant ephrins to a well-established calvarial model of bone growth to stimulate osteogenesis. Conversely, application of Eph extracellular domain protein will be used to competitively inhibit endogenous ephrins and thus block osteogenesis. These studies have both basic science and translational relevance in that they will establish the importance of, and potential application for, manipulation of Eph/ephrin signaling in the treatment of bone defects. Studies under the second aim will use previously characterized OB-specific promoter-driven luciferase reporters to identify the cis-acting elements within these promoters that are responsible for ephrin induction of gene transcription in OBs. This will lead to identification of transcription factors that may be amenable to manipulation in a clinical setting. The proposed work is innovative because it will uncover an entirely new role for Ephs in gene regulation, and will illuminate a novel mechanism for the regulation of osteogenesis. It will make a significant impact because of its potential to offer new therapeutic targets for the treatment of bone diseases. Public Health Relevance: The planned studies propose a heretofore-undescribed role for Eph/ephrin signaling in the regulation of gene expression. They have particular application to the public health in that they address basic mechanisms of osteoblast differentiation that are dysregulated in the pathogenesis of crippling bone diseases. Thus, they can be expected to contribute to advances in clinical treatment of these afflictions. Further, as ephrins are involved in virtually every stage of organogenesis, this work has the potential for broader impact on the fields of developmental and molecular biology.

描述（由申请人提供）：骨骼活力需要在整个生命过程中精确调节骨合成，伴随其失败的灾难性病理状况是一个重大的公共卫生挑战。然而，骨的合成通过来自周围组织的信号调节的机制尚不清楚，并且这种知识的缺乏阻碍了治疗骨生长缺陷疾病的能力。因此，该小组的长期目标是了解控制成骨细胞（OB），骨形成细胞分化的分子机制，以便在骨疾病的治疗中更好地操纵骨合成。最近的文献工作和本文提出的初步数据表明，并支持接触介导的促进OB分化的Eph受体酪氨酸激酶家族成员及其配体，肝配蛋白的核心作用。具体地：1）Ephs和肝配蛋白在体内骨生成的离散层中表达，和2）用可溶性重组肝配蛋白处理OB增加OB特异性基因表达和骨合成。基于这一证据，这一提议提出了Eph信号通过激活特定的成骨细胞基因启动子元件来调节骨生长的中心假设。拟议研究的基本原理是，更深入地了解这些受体如何参与接触介导的OB分化将揭示未来治疗中的控制点。这一假设将通过完成两个具体目标来解决：1）确定激活或阻断Eph信号传导对正常和有缺陷的骨形成的影响，以及2）确定特定启动子元件对OB基因激活的贡献。根据第一个目标的研究将应用重组肝配蛋白到一个成熟的颅骨骨生长模型，以刺激骨生成。相反，Eph胞外结构域蛋白的应用将用于竞争性抑制内源性肝配蛋白，从而阻断骨生成。这些研究具有基础科学和翻译相关性，因为它们将确立操纵Eph/ephrin信号传导在骨缺损治疗中的重要性和潜在应用。第二个目标下的研究将使用以前的特点OB-特异性启动子驱动的荧光素酶报告，以确定这些启动子内的顺式作用元件，负责肝配蛋白诱导基因转录在OB。这将导致识别的转录因子，可能是服从于在临床环境中操作。这项工作具有创新性，因为它将揭示Eps在基因调控中的全新作用，并将阐明骨生成调控的新机制。它将产生重大影响，因为它有可能为骨骼疾病的治疗提供新的治疗靶点。公共卫生相关性：计划中的研究提出了Eph/ephrin信号在基因表达调控中迄今未描述的作用。它们对公共卫生具有特别的应用，因为它们解决了成骨细胞分化的基本机制，所述成骨细胞分化在致残性骨疾病的发病机制中失调。因此，可以预期它们有助于这些疾病的临床治疗的进展。此外，由于肝配蛋白几乎参与器官发生的每个阶段，这项工作有可能对发育和分子生物学领域产生更广泛的影响。