Mechanical Signaling through Osteoblast Focal Adhesions

通过成骨细胞局部粘连的机械信号传导

基本信息

批准号：
7431790
负责人：
Fredrick M Pavalko
金额：
$ 28.64万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7431790
关键词：
Actinin Actins Address Adenoviruses Adhesions Atrophic Bed rest Binding Biochemical Cell Adhesion Molecules Cell Nucleus Cell Proliferation Regulation Cells Chronic Communication Condition Cytoplasmic Tail Data Doctor of Philosophy Dominant-Negative Mutation Environment Exhibits Extracellular Matrix Family Focal Adhesion Kinase 1 Focal Adhesions Gene Expression Gene Expression Regulation Goals In Vitro Insulin-Like Growth Factor I Insulin-Like Growth Factor Receptor Integrins Intercellular Fluid Knock-out Knockout Mice Liquid substance Mechanical Stimulation Mechanics Mechanoreceptors Mediating Metabolic Microgravity Mitogen-Activated Protein Kinases Molecular Movement Mus Nuclear Osteoblasts Osteocytes Phenotype Phosphotransferases Play Prostaglandin Production Prostaglandins Protein Overexpression Proto-Oncogene Proteins c-akt Publishing Rattus Research Personnel Role Signal Transduction Signal Transduction Pathway Signaling Molecule Site Skeletal system Space Flight Testing Transgenic Mice bone bone cell fluid flow human BCAR1 protein improved member novel programs research study response retinal rods shear stress transcription factor

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this proposal is understand the cellular mechanisms that mediate the anabolic response of bone to mechanical loading. Mechanical loading of bone induces the movement of interstitial fluid within the spaces inside bone. The resulting mechanical stimulation of osteoblasts and osteocytes caused by fluid shear stress (FSS) is hypothesized to play a role in the response of bone to mechanical loading. Support for this hypothesis comes from the observation that osteoblasts and osteocytes that are stimulated by FSS in vitro exhibit increased metabolic activity compared to cells that are maintained under static culture conditions. The central focus of this application is to determine the cellular mechanisms that mediate the mechanical sensitivity of bone cells to their local environment. Specifically, we propose to examine the role of adhesion sites (commonly referred to as focal contacts or focal adhesions) between osteoblasts and osteocytes to the extracellular matrix that are mediated by integrin cell adhesion molecules in regulating the response of bone cells to FSS. The results of this study should provide an improved understanding of the fundamental cellular and molecular mechanisms that mediate the response of bone cells to mechanical loading by testing the hypothesis that focal adhesions function as mechanoreceptors by coordinating the activity of cytoplasmic signaling molecules that interact with integrins. Physiologically relevant responses by bone cells to unidirectional and oscillatory fluid flow include altered proliferative activity and enhanced differentiation toward an anabolic or osteoblastic phenotype, altered gene expression, increased prostaglandin production, activation of mitogen activated protein kinases (MAPK) and focal adhesion kinase (FAK) and sensitization of the insulin-like growth factor receptor (IGF-1R) to stimulation by IGF-1. Three specific aims are proposed. In Aim 1 we will determine the effect of disrupting the structural integrity of focal adhesions on biochemical response of osteoblasts to FSS. In Aim 2 we will determine the role of focal adhesion kinase (FAK) mediated signal transduction pathways activated by FSS in mechanotransduction. In Aim 3 we will determine the role of the transcription factor NMP4/CIZ in mediating signal transduction pathways activated through focal adhesions in response to fluid shear stress. Together these studies should provide novel information on the cellular mechanisms that mediate mechanotransduction in bone.

描述（由申请人提供）：该提案的总体目标是了解介导骨骼对机械负荷的合成代谢反应的细胞机制。骨的机械负荷引起骨内空间内的间质液的运动。据推测，由流体剪切应力（FSS）引起的成骨细胞和骨细胞的机械刺激在骨对机械载荷的响应中发挥作用。这一假设的支持来自于以下观察：与静态培养条件下维持的细胞相比，在体外受 FSS 刺激的成骨细胞和骨细胞表现出更高的代谢活性。该应用的中心重点是确定介导骨细胞对其局部环境的机械敏感性的细胞机制。具体来说，我们建议检查成骨细胞和骨细胞之间的粘附位点（通常称为焦点接触或粘着斑）与细胞外基质的作用，这些粘附位点由整联蛋白细胞粘附分子介导，在调节骨细胞对 FSS 的反应中发挥作用。这项研究的结果应该通过测试粘着斑通过协调与整合素相互作用的细胞质信号分子的活性而发挥机械感受器作用的假设，从而更好地理解介导骨细胞对机械负荷的反应的基本细胞和分子机制。骨细胞对单向和振荡流体流的生理相关反应包括改变增殖活性和增强向合成代谢或成骨细胞表型的分化、改变基因表达、增加前列腺素产生、激活丝裂原激活蛋白激酶（MAPK）和粘着斑激酶（FAK）胰岛素样生长因子受体 (IGF-1R) 对 IGF-1 刺激的敏感性。提出了三个具体目标。在目标 1 中，我们将确定破坏粘着斑结构完整性对成骨细胞对 FSS 的生化反应的影响。在目标 2 中，我们将确定 FSS 激活的粘着斑激酶 (FAK) 介导的信号转导途径在机械转导中的作用。在目标 3 中，我们将确定转录因子 NMP4/CIZ 在介导通过粘着斑响应流体剪切应力而激活的信号转导途径中的作用。这些研究共同应提供有关介导骨骼机械力转导的细胞机制的新信息。