Dynamics of Assembly of Bone Matrix Proteins
骨基质蛋白组装动力学
基本信息
- 批准号:7871226
- 负责人:
- 金额:$ 0.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-14 至 2009-10-31
- 项目状态:已结题
- 来源:
- 关键词:AddressArthritisBindingBinding ProteinsBiological AvailabilityBone MatrixBone remodelingCell Culture TechniquesCell modelCellsComplexComputer AnalysisDataDepositionDiseaseEventExtracellular MatrixExtracellular Matrix ProteinsFibroblastsFibronectinsFoundationsGlycoproteinsGrowth FactorImageIn VitroKnock-outLaboratoriesLifeMalignant NeoplasmsMeasuresMediatingModelingMolecularMorphogenesisMovementMusNull LymphocytesOsteoblastsOsteogenesisOsteoporosisPathway interactionsPlayProcessProteinsRegulationReporterRheumatoid ArthritisRoleSiteSkeletal DevelopmentStructureSupporting CellTNFRSF1A geneTestingTimeTissuesTransforming Growth Factor betabasebonecell motilityin vivoinsightmineralizationmolecular imagingnovelrepairedresponsescaffold
项目摘要
DESCRIPTION (provided by applicant): The extracellular matrix (ECM) has classically been viewed as a static scaffold that provides support to cells and tissues. However, recent studies have shown that ECM molecules form highly dynamic structures that continually undergo movement and deformation in response to cell movement. Evidence is accumulating that ECM proteins may also be major regulators of growth factor activity. Fibronectin is one of the earliest ECM proteins to be assembled into the matrix and facilitates assembly of other ECM proteins. Using a fibronectin null cell model we have found that fibronectin is essential for assembly of multiple bone ECM proteins and is required for osteoblast mineralization but not differentiation. Fibronectin is also critical for assembly of latent TGF( binding protein-1 (LTBP1), an important regulator of TGF(, into the ECM. In addition, our recent dynamic imaging studies in living osteoblasts have suggested novel roles for cell movement in bone ECM assembly and reorganization.
The proposed studies are centered around two main hypotheses. The first is that fibronectin is a multifunctional regulator of osteoblast function through its effects as an orchestrator of assembly of bone ECM proteins and through regulation of growth factor activity. The second is that dynamic cell movement is essential for the assembly and reorganization of bone ECM proteins. To test these hypotheses complimentary in vitro and in vivo approaches will be used. In Aim 1 we will determine the role of fibronectin in osteoblast function through its role as a regulator of assembly of bone ECM proteins. Fibronectin-null osteoblast culture models will be used in conjunction with a conditional knockout approach to delete fibronectin in the osteoblast lineage. In Aim 2 we will determine the role of fibronectin in regulating TGF( activity in bone via interactions with LTBP1. This will be done using fibronectin null osteoblasts as well as a novel TGF( reporter mouse line that can be used to measure in vivo TGF( activity. In Aim 3 we will determine the dynamics of assembly and reorganization of bone ECM proteins and their interactions with fibronectin and determine the role of cell movement in ECM assembly and reorganization. This will be done using dynamic molecular imaging of bone ECM proteins together with quantification of cell and fibril dynamics by computational analysis. These studies will provide novel insights into the mechanisms of assembly of bone ECM proteins and provide new insights into the complex molecular pathways for ECM regulation of TGF( in bone. The data generated will have important implications for diseases associated with misregulation of TGF(, such as fibrotic diseases, osteoporosis, arthritis and cancer.
描述(申请人提供):细胞外基质(ECM)被经典地视为为细胞和组织提供支持的静态支架。然而,最近的研究表明,细胞外基质分子形成高度动态的结构,随着细胞的运动而不断发生运动和变形。越来越多的证据表明,ECM蛋白也可能是生长因子活性的主要调节因子。纤维连接蛋白是最早被组装到基质中的ECM蛋白之一,它促进了其他ECM蛋白的组装。利用纤维连接蛋白缺失的细胞模型,我们发现纤维连接蛋白对多种骨ECM蛋白的组装是必不可少的,并且是成骨细胞矿化所必需的,但不是分化所必需的。纤维连接蛋白也是潜在的转化生长因子结合蛋白-1(LTBP1)--转化生长因子的重要调节因子--组装到细胞外基质中的关键。此外,我们最近对活体成骨细胞的动态成像研究表明,细胞运动在骨细胞外基质组装和重组中扮演了新的角色。
拟议的研究围绕两个主要假设展开。首先,纤维连接蛋白是一种多功能的成骨细胞功能调节剂,它通过作为骨ECM蛋白组装的协调者和通过调节生长因子的活性来发挥作用。第二,细胞的动态运动对于骨细胞外基质蛋白的组装和重组是必不可少的。为了检验这些假说,将使用体外和体内互补的方法。在目标1中,我们将通过调节骨ECM蛋白的组装来确定纤维连接蛋白在成骨细胞功能中的作用。纤维连接蛋白缺失的成骨细胞培养模型将与条件基因敲除方法结合使用,以删除成骨细胞谱系中的纤维连接蛋白。在目标2中,我们将通过与LTBP1的相互作用来确定纤维连接蛋白在调节骨骼中的转化生长因子活性中的作用。这将使用纤维连接蛋白缺失的成骨细胞以及一种新型的可用于测量体内转化生长因子活性的报告鼠系来完成。在目标3中,我们将确定骨细胞外基质蛋白的组装和重组的动力学及其与纤维连接蛋白的相互作用,并确定细胞运动在细胞外基质组装和重组中的作用。这将使用骨细胞外基质蛋白的动态分子成像以及通过计算分析对细胞和纤维动力学进行量化来完成。这些研究将为了解骨细胞外基质蛋白的组装机制提供新的见解,并为骨组织中细胞外基质调节转化生长因子的复杂分子途径提供新的见解。生成的数据将对与转化生长因子(TGF)调控不当相关的疾病产生重要影响,如纤维性疾病、骨质疏松症、关节炎和癌症。
项目成果
期刊论文数量(0)
专著数量(0)
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