Proteoglycan Regulation of Growth Plate Cartilage Calcification
生长板软骨钙化的蛋白多糖调节
基本信息
- 批准号:7674929
- 负责人:
- 金额:$ 4.93万
- 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:2009-04-01 至 2012-03-31
- 项目状态:已结题
- 来源:
- 关键词:AchondroplasiaAffectAnimal ModelBehaviorBone DevelopmentBone GrowthCalcifiedCalpainCartilageCartilage injuryCathepsinsCell Culture TechniquesCell LineCell ProliferationCellsChondrocytesChondroitin SulfatesChondroitinasesClinicalComplexCongenital AbnormalityCysteine ProteaseDataDeformityDegenerative polyarthritisDisintegrinsDysplasiaElderlyEpiphysial cartilageEquilibriumFracture HealingFunctional disorderGene TargetingGlycosaminoglycansGoalsGrowthHyaluronanHyaluronidaseHypertrophyHypophosphatasiaImmuneIn VitroInheritedKeratan SulfateKnock-outLaboratoriesLengthMatrix MetalloproteinasesMediatingMesenchymalMetalloproteasesMineralsModelingModificationMonoclonal AntibodiesMorphologyMusNutritionalOsteocalcinPathway interactionsPatternPeptide HydrolasesPhosphoproteinsPhysiologic calcificationPhysiologicalProcessProteinase 3ProteinsProteoglycanRNA InterferenceRegulationResearchRicketsRoleSiteSkeletonSolutionsStagingStructureSyndromeSystemTerm BirthTestingThanatophoric DysplasiaTimeTissue EngineeringTissuesWorkaggrecanaggrecanasebonecalcificationcathepsin Kchondrodysplasiacytokinekeratan-sulfate endo-1,4-b-galactosidaseknock-downknockout animallink proteinlong bonemineralizationosteopontinpreventrepairedresearch studysodium chloratesulfationsulfotransferasetreatment effect
项目摘要
DESCRIPTION (provided by applicant): Endochondral ossification is a very complex process and a great deal of research has determined that proteoglycans (PCs) have a critical role in cartilage calcification during this process. Previous work has demonstrated that PG aggregate size is a key regulator of crystal size and proliferation in calcified cartilage. Additionally, several knockout animal models have suggested that PG synthesis, structure, and degradation are intimately related to cartilage mineralization in the process of endochondral ossification. PG modification also influences the activity of surrounding cytokines, such as phosphoproteins. However, the mechanism by which PG morphology is regulated during cartilage calcification is still unknown. Thus we hypothesize that aggrecan modification is required for physiologic cartilage calcification to occur and that a delicate balance exists between proteoglycan morphology and protein activity ultimately resulting in cartilage calcification. To test these hypotheses, we propose to use a mouse mesenchymal cell line previously demonstrated to recapitulate the process of endochondral ossification in micromass culture. Our Specific Aims are to: 1) To determine the mechanism of aggrecan turnover within the growth plate. During different stages of chondrocyte maturation, the micromass system will be probed with monoclonal antibodies developed for specific neoepitopes that result from cleavage of aggrecan by MMPs, ADAMTSs, and cysteine proteases. 2) To test the hypothesis that aggrecan modification is required for physiologic cartilage calcification to occur using a combination of immune-blocking and RNAi knock down experiments for aggrecanolytic proteinases. 3) To determine the relationship between the degree and type of aggrecan sulfation and cartilage calcification. Micromass cultures will be treated with sodium chlorate (NaCIO3) to inhibit glycosaminoglycan sulfation of aggrecan, chondroitinase to release chondroitin sulfate (CS), or keratanase to release keratan sulfate (KS) chains from the matrix. The effects of these treatment groups on aggrecanolytic proteinase and phosphoprotein activity will be assessed. Conditions in which cartilage calcification is aberrant affect both the new born and the elderly in terms of birth defects, growth deformities, and inherited abnormalities. To prevent and treat these conditions it is essential to understand physiologic cartilage calcification. The ultimate goal of these studies is to understand the mechanisms involved in physiologic cartilage calcification during endochondral bone growth using a cell culture model. Using this information, target genes or biomolecules may be identified so that clinical solutions that treat the functional disorders of cartilage tissue may be developed.
描述(由申请人提供):软骨内骨化是一个非常复杂的过程,大量研究已经确定蛋白多糖(PC)在此过程中的软骨钙化中发挥着关键作用。先前的研究表明,PG 聚集体大小是钙化软骨晶体大小和增殖的关键调节因子。此外,一些基因敲除动物模型表明PG的合成、结构和降解与软骨内骨化过程中的软骨矿化密切相关。 PG 修饰还会影响周围细胞因子的活性,例如磷蛋白。然而,软骨钙化过程中PG形态的调节机制仍不清楚。因此,我们假设软骨聚集蛋白聚糖修饰是生理性软骨钙化发生所必需的,并且蛋白多糖形态和蛋白质活性之间存在微妙的平衡,最终导致软骨钙化。为了检验这些假设,我们建议使用先前证明的小鼠间充质细胞系来重现微团培养中软骨内骨化的过程。我们的具体目标是: 1) 确定生长板内聚集蛋白聚糖周转的机制。在软骨细胞成熟的不同阶段,将使用针对特定新表位开发的单克隆抗体来探测微团系统,这些新表位是由 MMP、ADAMTS 和半胱氨酸蛋白酶切割聚集蛋白聚糖而产生的。 2) 为了检验聚集蛋白聚糖修饰是生理性软骨钙化发生所必需的假设,使用聚集蛋白聚糖分解蛋白酶的免疫阻断和 RNAi 敲低实验相结合。 3)确定聚集蛋白聚糖硫酸化程度和类型与软骨钙化之间的关系。将用氯酸钠(NaCIO 3 )处理微团培养物以抑制聚集蛋白聚糖的糖胺聚糖硫酸化,用软骨素酶处理以释放硫酸软骨素(CS),或用角质酶处理以从基质中释放硫酸角质素(KS)链。将评估这些治疗组对聚集蛋白水解蛋白酶和磷蛋白活性的影响。软骨钙化异常的情况会影响新生儿和老年人的出生缺陷、生长畸形和遗传异常。为了预防和治疗这些疾病,了解生理性软骨钙化至关重要。这些研究的最终目标是利用细胞培养模型了解软骨内骨生长过程中生理软骨钙化的机制。利用这些信息,可以鉴定靶基因或生物分子,从而可以开发治疗软骨组织功能障碍的临床解决方案。
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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Rhima Coleman其他文献
Rhima Coleman的其他文献
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{{ truncateString('Rhima Coleman', 18)}}的其他基金
Autonomous RUNX2 suppression in genetically modified stem cell-derived chondrocytes as a disease modifying therapeutic for PTOA
转基因干细胞衍生软骨细胞中的自主 RUNX2 抑制作为 PTOA 的疾病修饰疗法
- 批准号:
10574780 - 财政年份:2023
- 资助金额:
$ 4.93万 - 项目类别:
Proteoglycan Regulation of Growth Plate Cartilage Calcification
生长板软骨钙化的蛋白多糖调节
- 批准号:
8037730 - 财政年份:2009
- 资助金额:
$ 4.93万 - 项目类别:
Proteoglycan Regulation of Growth Plate Cartilage Calcification
生长板软骨钙化的蛋白多糖调节
- 批准号:
7800300 - 财政年份:2009
- 资助金额:
$ 4.93万 - 项目类别:
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