Controlling chondrocyte matrix degradation and repair in 3-D culture.
控制 3D 培养中的软骨细胞基质降解和修复。
基本信息
- 批准号:8213730
- 负责人:
- 金额:$ 5.22万
- 依托单位:
- 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:2010-02-01 至 2013-01-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAdherent CultureAdultAffectAlginatesAmericanApoptosisArthritisBiocompatibleCartilageCartilage injuryCattleCellsChemicalsChondrocytesCollagenDataDefectDegenerative polyarthritisDepositionDevelopmentDimensionsDiseaseDoseElementsEmbryoEngineeringEnvironmental Risk FactorEventExtracellular MatrixGene TargetingGenerationsGenesGeneticGenetic DeterminismGenetic ProgrammingGlycosaminoglycansGoalsGrowthHarvestHypertrophyImageIn VitroInflammatoryInjuryKnock-outKnockout MiceKnowledgeLaboratoriesMAP Kinase GeneMAP2K6 geneMAPK14 geneMAPK8 geneMAPK9 geneMEKsMechanicsMentorsMethodsMicroscopyMissionModelingMusMutationNF-kappa BNFKB Signaling PathwayNational Institute of Arthritis and Musculoskeletal and Skin DiseasesOperative Surgical ProceduresPathway interactionsPeptide HydrolasesPharmacologic SubstancePhenotypePopulationProceduresProcessProductionPropertyProteoglycanRelative (related person)ResearchSignal PathwaySignal TransductionSolutionsStressStructureSystemTNF geneTechniquesThinkingTimeTissue EngineeringTissuesTrainingTransgenic OrganismsTraumaTumor Necrosis Factor-alphaUnited States National Institutes of HealthWeight-Bearing stateaggrecanarticular cartilagebasecareercartilage developmentcartilage repaircrosslinkexperiencegene therapyhuman TNF proteinin vitro Modelknockout genemathematical modelmultidisciplinarynovelosteochondral repairosteochondral tissueprogramsrepairedresponsescaffoldsecond harmonicskillstooltwo-photon
项目摘要
DESCRIPTION (provided by applicant): This proposal's long-term objectives are: 1) to provide basic knowledge about how manipulation of Inflammatory signaling pathways can affect the mechanical properties of chondrocyte created neo-matrix, and 2) to create a tissue-engineered surgical solution to restore osteochondral defects. These objectives will be through two specific aims: construction and analysis of tissue-engineered cartilage using 1) genetically-modified mouse chondrocytes with knockout of MKK/MEK3; and 2) pharmacologic inhibition of key signaling pathways (p38 and JNK MARK) that regulate proteoglycan and collagen deposition by chondrocytes in tissue-engineered cartilage. Analysis will encompass mechanical characterization, collagen, crosslink, and GAG content, multiphoton microscopy, and mathematical modeling of the tissue. The goals of this proposal are relevant to the mission of the NIH and NIAMS. Functional engineered cartilage would greatly alleviate cartilage damage which affects ~10% of the population (1). Information gained about the genetic determinants of cartilage neo-matrix formation would increase understanding of cartilage degradation in rheumatoid and osteoarthritis. This proposal has tissue engineering, multiphoton imaging, and mathematical modeling components, and is a multidisciplinary effort to advance basic knowledge of chondrocyte genetic programming in disease and repair processes. Chondrocytes from mice with knockouts and mutations of TNF-alpha and IL-1beta signaling elements will be harvested and seeded within alginate scaffolds to allow neo-matrix development. Tissue mechanical properties, collagen, proteoglycan, and crosslink content will be assessed during culture under normal and transgenic phenotype, and with or without pharmacologic inhibition of the same signaling pathways, known to affect extracellular matrix production (2). Multiphoton imaging will be used to assess collagen deposition and network structure (using signal from second harmonic generation) and collagen crosslink formation (through two-photon autofluorescence signal). Data from the tissue-engineered cartilage will be fit to a cartilage growth mixture model, previously developed to assess native cartilage (3). Every year, cartilage Injury affects nearly 1 million Americans resulting in 200,000 procedures. Injury often leads cryptically to osteoarthritis (1). Tissue-engineered cartilage is a promising method to examine chondrocyte-controlled cartilage degradation and repair. Understanding these processes in vitro would help clinicians control and repair cartilage through pharmaceutical, genetic, and surgical manipulations.
描述(由申请人提供):该提案的长期目标是:1)提供关于炎症信号通路的操纵如何影响软骨细胞产生的新基质的机械特性的基本知识,以及2)创建组织工程化手术解决方案以恢复骨软骨缺损。这些目标将通过两个具体目标实现:使用1)MKK/MEK 3敲除的遗传修饰小鼠软骨细胞构建和分析组织工程化软骨;以及2)对组织工程化软骨中软骨细胞调节蛋白聚糖和胶原沉积的关键信号通路(p38和JNK MARK)的药理学抑制。分析将包括机械表征、胶原蛋白、交联和GAG含量、多光子显微镜和组织数学建模。 该提案的目标与NIH和NIAMS的使命相关。功能性工程软骨将大大减轻软骨损伤,影响约10%的人口(1)。关于软骨新基质形成的遗传决定因素的信息将增加对类风湿和骨关节炎中软骨退化的理解。该提案具有组织工程,多光子成像和数学建模组件,是一项多学科的努力,以推进疾病和修复过程中软骨细胞遗传编程的基础知识。 将收获来自TNF-α和IL-1 β信号传导元件敲除和突变的小鼠的软骨细胞,并接种在藻酸盐支架内,以允许新基质发育。在正常和转基因表型下培养期间,在存在或不存在已知影响细胞外基质产生的相同信号传导途径的药理学抑制的情况下,评估组织机械特性、胶原蛋白、蛋白聚糖和交联含量(2)。多光子成像将用于评估胶原沉积和网络结构(使用二次谐波产生的信号)和胶原交联形成(通过双光子自体荧光信号)。来自组织工程化软骨的数据将拟合到先前开发用于评估天然软骨的软骨生长混合物模型(3)。 每年,软骨损伤影响近100万美国人,导致20万例手术。损伤往往导致神秘的骨关节炎(1)。组织工程化软骨是研究软骨细胞控制的软骨降解和修复的一种很有前途的方法。了解这些过程在体外将有助于临床医生控制和修复软骨通过药物,遗传和手术操作。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Christopher B Raub其他文献
Christopher B Raub的其他文献
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{{ truncateString('Christopher B Raub', 18)}}的其他基金
A high throughput, in vitro screening system for treatments of oral mucositis in cancer
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- 批准号:
10041746 - 财政年份:2020
- 资助金额:
$ 5.22万 - 项目类别:
A high throughput, in vitro screening system for treatments of oral mucositis in cancer
用于治疗癌症口腔粘膜炎的高通量体外筛选系统
- 批准号:
10251272 - 财政年份:2020
- 资助金额:
$ 5.22万 - 项目类别:
A dual-modality quantitative phase and polarized light microscope to assess cell motility and extracellular matrix remodeling during invasion
双模态定量相和偏光显微镜评估侵袭过程中的细胞运动和细胞外基质重塑
- 批准号:
9924599 - 财政年份:2019
- 资助金额:
$ 5.22万 - 项目类别:
Controlling chondrocyte matrix degradation and repair in 3-D culture.
控制 3D 培养中的软骨细胞基质降解和修复。
- 批准号:
7807636 - 财政年份:2010
- 资助金额:
$ 5.22万 - 项目类别:
Controlling chondrocyte matrix degradation and repair in 3-D culture.
控制 3D 培养中的软骨细胞基质降解和修复。
- 批准号:
8035903 - 财政年份:2010
- 资助金额:
$ 5.22万 - 项目类别:
Multiphoton Imaging and Rheology of Fibrosis Models
纤维化模型的多光子成像和流变学
- 批准号:
7407804 - 财政年份:2007
- 资助金额:
$ 5.22万 - 项目类别:
Multiphoton Imaging and Rheology of Fibrosis Models
纤维化模型的多光子成像和流变学
- 批准号:
7496521 - 财政年份:2007
- 资助金额:
$ 5.22万 - 项目类别:
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