Mechanisms Regulating Formation and Growth of Articular Cartilage

调节关节软骨形成和生长的机制

• 批准号: 10001438
• 负责人: Danielle Renae Rux
• 金额: $ 6.74万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001438
• 关键词: Ablation; Adult; Affect; Age; Anatomy; Area; Articular Range of Motion; Attention; Autologous; Biomechanics; Biomedical Engineering; Birth; Cartilage; Cell Culture System; Cell Culture Techniques; Cell Polarity; Cell Proliferation; Cell Transplantation; Cell Volumes; Cells; Cellularity; Chondrocytes; Clinical; Data; Degenerative polyarthritis; Development; Developmental Biology; Disease; Embryo; Embryonic Development; Environment; Fibrocartilages; Friction; Future; Gene Expression Profile; Genes; Genetic; Growth; Image; In Situ Hybridization; Injury; Intervention; Joint repair; Joints; Knee; Knowledge; Lasers; Life; Ligaments; Limb structure; Location; Locomotion; Lubricants; Minor; Molecular; Morphogenesis; Motion; Movement; Mus; Neonatal; Osteochondritis Dissecans; Pathology; Pathway interactions; Pattern; Phenotype; Play; Process; Property; Quality of life; Quantitative Reverse Transcriptase PCR; ROR2 gene; Reporter; Research; Role; Shoulder; Structure; Surface; Synovial joint; Territoriality; Testing; Therapeutic; Thick; Thinness; Three-Dimensional Imaging; Time; Tissues; Transgenic Mice; WNT Signaling Pathway; Work; age related; analytical tool; arthropathies; articular cartilage; base; bone; calcification; capsule; career; cartilage development; cartilage regeneration; cartilage repair; cohort; confocal imaging; design; effective therapy; flexibility; gene therapy; human tissue; image reconstruction; improved; in vivo; insight; intercalation; joint function; mechanical load; mouse model; mutant; novel; organ growth; planar cell polarity; polarized cell; postnatal; repaired; resilience; skeletal movement; spatiotemporal; tissue regeneration; tool; translational medicine

Project Summary/Abstract Synovial joints are essential for full range of motion and quality of life. Each joint is uniquely shaped to fit specific anatomical sites and permit relevant body movement and function. Unfortunately, the joints -and articular cartilage in particular- are highly susceptible to congenital-, injury- and age-related diseases that affect their structure and function, also a reflection of poor intrinsic joint repair capacity. In addition, current clinical interventions do not meet the wide range of demands on articular cartilage in vivo due, in large part, to lack of crucial knowledge on the mechanisms that govern normal growth and structure of the tissue. In order to advance these strategies, more information is needed on basic mechanisms of articular cartilage development, growth and morphogenesis. Were such information available, it would inform the improvement of clinical intervention, and bioengineering and gene therapy strategies as has been accomplished in disease- and injury- related treatment of many other human tissues. Articular cartilage is uniquely organized and displays distinct zones each providing specific and important functions for the synovial joint: (i) surface zone cells secrete lubricants into the joint cavity; (ii) deep zone cells are organized in columns to resist compressive loads; and (iii) a calcified cartilage zone provides attachment of the tissue to the underlying bone. Little is known about the mechanisms that drive this specific organization. Recent work from my sponsor and colleagues has improved our understanding of postnatal articular development using genetic lineage-tracing tools in mouse models. The data show that cell proliferation plays a more minor role in articular cartilage postnatal growth than previously thought and suggest, instead, that cell translocation and realignment are major drivers of growth and organization. Based on the results from these novel studies, I hypothesize that articular cartilage formation and growth mechanisms are primarily driven by cell intercalation and realignment into stacks and columns, permitting tissue thickening and organization. To test this hypothesis, in Aim 1 I will examine the spatio-temporal expression patterns of genes relevant to, and regulating, cell intercalation and alignment mechanisms. In Aim 2 I will test the function of core components of these pathways that have proven critical for organization and growth in other tissue contexts. I will use multiple analytical tools including histomorphometry, in situ hybridization, confocal imaging and cell culture in combination with mouse transgenic approaches. The proposed studies will provide essential knowledge on mechanisms that underlie the acquisition of articular cartilage structure and function. The data and insights from the project will prove essential to envision and test future therapeutic joint strategies, providing broad relevance and importance to the project and offering a powerful and encompassing platform for establishing my independent career in biomedical and translational medicine research.

项目总结/摘要 滑膜关节对于全方位的运动和生活质量至关重要。每个关节的形状都很独特 特定的解剖部位，并允许相关的身体运动和功能。不幸的是，关节-和 特别是关节软骨-对先天性、损伤和年龄相关疾病非常敏感， 影响其结构和功能，也反映了关节内在修复能力差。此外，目前 在很大程度上，由于 缺乏关于控制组织正常生长和结构的机制的关键知识。为了 推进这些策略，需要更多关于关节软骨发育基本机制的信息， 生长和形态发生。如果有这样的信息，它将有助于改善临床 干预、生物工程和基因治疗策略，如在疾病和损伤方面所取得的成就， 许多其他人体组织的相关治疗。关节软骨组织独特， 每个区为滑膜关节提供特定和重要的功能：（i）表面区细胞分泌 （ii）深层细胞被组织成柱以抵抗压缩载荷;以及 (iii)钙化的软骨区提供组织与下面的骨的附着。知之甚少 驱动这个特定组织的机制。我的赞助商和同事最近的工作 使用小鼠遗传谱系追踪工具提高了我们对出生后关节发育的理解 模型这些数据表明，细胞增殖在关节软骨出生后的生长中起着更小的作用 相反，细胞移位和重新排列是 成长和组织。根据这些新研究的结果，我假设关节软骨 形成和生长机制主要由电池嵌入和重新排列成叠层驱动， 柱状，允许组织增厚和组织化。为了验证这个假设，在目标1中，我将检查 与细胞嵌入和排列相关并调节细胞嵌入和排列的基因的时空表达模式 机制等在目标2中，我将测试这些已被证明至关重要的途径的核心组件的功能 在其他组织环境中的组织和生长。我将使用多种分析工具，包括 组织形态计量学、原位杂交、共聚焦成像和细胞培养结合小鼠 转基因方法拟议的研究将提供有关机制的基本知识， 关节软骨结构和功能的获得。该项目的数据和见解将证明 至关重要的是，设想和测试未来的治疗联合战略，提供广泛的相关性和重要性， 该项目，并提供了一个强大的和包容的平台，建立我的独立职业生涯， 生物医学和转化医学研究。