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GENE EXPRESSION PATTERNS IN OSTEOCYTES IN RESPONSE TO LOAD

骨细胞响应负荷的基因表达模式

基本信息

批准号：
7435363
负责人：
STEPHEN Eubank HARRIS
金额：
$ 20.64万
依托单位：
UNIVERSITY OF MISSOURI KANSAS CITY
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：
2007-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7435363
关键词：
3-Dimensional Animal Model Biochemical Bioinformatics Biological Biological Assay Biology Bone Diseases Bone Resorption Bone Surface Canis familiaris Cell model Cell physiology Cells Collaborations Condition DNA Databases Defect Dominant Genes Dominant-Negative Mutation DsRed Engineering Enhancers Environment Extracellular Matrix Family Fatigue Femur Foundations Fracture Gene Activation Gene Expression Gene Expression Profiling Genes Genetic Genetic Transcription Genome Genomics Giant Cells Goals Green Fluorescent Proteins Human Image In Situ In Situ Hybridization In Vitro Individual Knock-out Knockout Mice Lead Link Liquid substance Localized Maps Measurement Measures Mechanical Stimulation Mechanics Microarray Analysis Modeling Modification Molecular Molecular Profiling Morphology Mus Mutant Strains Mice Nucleic Acid Regulatory Sequences Osteoblasts Osteocytes Osteogenesis Osteoporosis Output Pathway interactions Pattern Pharmaceutical Preparations Physiological Play Population Postmenopausal Osteoporosis Prevention Process Property Proteins Reading Reporter Research Research Personnel Resistance Role Siblings Signal Transduction Site Skeletal system Skeleton Standards of Weights and Measures System Systems Biology Testing Thinking Tissues Transgenic Organisms Validation Wild Type Mouse Work bone bone cell bone disuse atrophy bone loss chromatin immunoprecipitation dentin matrix protein 1 experience genetic regulatory protein in vivo indexing inhibitor/antagonist insight member mineralization mouse model neuronal cell body prevent programs promoter rat genome release factor response selective expression tool transcription factor ulna

项目摘要

It is now known that small changes in bone adaption to mechanical load can lead to large changes in skeletal resistance to fracture. Osteocytes are believed to be the mechanosensory cells of bone receiving these physiological signals and responding in a manner to regulate their local microenvironment and to globally control bone formation and bone resorption in selective regions of bone. Dentin Matrix Protein 1, DMP1, and Matrix Extracellular Phosphoglycoprotein, MEPE, are highly expressed in osteocytes and respond to mechanical load. Both proteins are highly localized in the canaliculi and lacunae of osteocytes, with DMP1 found predominately on the canalicular walls. Our goal is to use these two genes as representative of osteocyte selective genes responsive to mechanical strain to identify molecular signalling mechanisms responsible for changes in bone properties. Our hypothesis is that specific osteocyte selective and mechanically responsive enhancer regions exist in the promoters of DMP1 and MEPE that are controlled by specific transcription family pathways in response to strain. To test this hypothesis three specific aims are proposed: Specific Aim 1. Determine the relationship between DMP1 and MEPE gene expression patterns with strain field analysis upon mechanical loading in vivo. Specific Aim 2. Determine the relationship of osteocyte deformation in the mouse ulna and femur to different levels of strain and gene activation of the DMP1 and MEPE cis-regulatory regions. Specific Aim 3. Determine the cis-regulatory regions of the DMP1 and MEPE genes that control the response to loading selectively in osteocytes. This project is unique in that DMP1 and MEPE gene expression will be correlated with macroscopic strain in vivo and with local cell deformation ex vivo. These genes and their appropriate cis-regulatory regions linked to reporters will serve as sensitive read-outs of osteocyte responsiveness in different loading conditions in different genetic backgrounds. This project will be devoted to understanding the cis-regulatory systems of both the DMP1 and MEPE genes in terms of their osteocyte selectivity and to identifying transcription factors responsible for this selectivity and responsiveness to mechanical loading. The goals of this project will be accomplished using cell models to identify molecular mechanisms, animal models for in vivo validation, together with engineering principles, combined with a molecular and a systems biology approach. Increased fatigue resistance is a major means to prevent fracture. Mapping osteocyte genes and pathways that are selectively responsive to load will provide information important to prevention or treatment of bone disease such as disuse osteoporosis, post menopausal osteoporosis and other pathological conditions of bone loss.

现在已知，骨骼对机械负荷的适应的微小变化可能会导致骨骼适应能力的巨大变化。骨骼的抗骨折能力。骨细胞被认为是骨接收的机械感觉细胞这些生理信号并以调节其局部微环境的方式做出反应全局控制骨的选择性区域的骨形成和骨吸收。牙本质基质蛋白1， DMP1 和基质细胞外磷酸糖蛋白 (MEPE) 在骨细胞中高度表达，响应机械负载。两种蛋白质都高度定位于骨细胞的小管和腔隙中， DMP1 主要存在于小管壁上。我们的目标是利用这两个基因代表对机械应变响应的骨细胞选择性基因，以识别分子信号传导负责骨特性变化的机制。我们的假设是特定的骨细胞选择性 DMP1 和 MEPE 的启动子中存在机械响应增强子区域由特定转录家族途径控制以响应菌株。为了检验这个假设三提出具体目标：具体目标1.确定DMP1和MEPE基因之间的关系体内机械负荷下应变场分析的表达模式。具体目标 2. 确定小鼠尺骨和股骨骨细胞变形与不同水平应变和基因的关系 DMP1 和 MEPE 顺式调控区的激活。具体目标 3. 确定顺式监管 DMP1 和 MEPE 基因的区域选择性地控制骨细胞中的负载反应。这该项目的独特之处在于DMP1和MEPE基因表达将与体内宏观应变相关并伴有离体局部细胞变形。这些基因及其适当的顺式调控区域与报告器将作为不同负载条件下骨细胞反应性的敏感读数不同的遗传背景。该项目将致力于了解顺式监管体系 DMP1 和 MEPE 基因在骨细胞选择性和识别转录因子方面的作用负责这种选择性和对机械负载的响应。该项目的目标将是使用细胞模型来识别分子机制，使用动物模型进行体内验证，结合工程原理，结合分子和系统生物学方法。提高抗疲劳能力是防止断裂的主要手段。绘制骨细胞基因图谱对负荷有选择性响应的途径将提供对预防或治疗重要的信息废用性骨质疏松症、绝经后骨质疏松症等病理性骨病的治疗骨质流失的情况。