Tendon Enthesis Development and Regeneration

肌腱附着点的发育和再生

• 批准号: 8910865
• 负责人: Stavros Thomopoulos
• 金额: $ 40.68万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8910865
• 关键词: Adult; Anterior Cruciate Ligament; Biochemical; Bone Regeneration; Botulinum Toxins; Boxing; Brachial plexus structure; Cartilage; Cell Lineage; Cell Maintenance; Cells; Chondrocytes; Cicatrix; Collagen Fiber; Collagen Type I; Cues; Data; Defect; Development; Differentiation Antigens; Diphtheria Toxin; Embryo; Embryonic Development; Erinaceidae; Event; Exhibits; Extracellular Matrix; Failure; Fibroblasts; Fibrocartilages; Future; Genetic; Goals; Growth Factor; Healed; Health; Individual; Injury; Knee; Knockout Mice; Lead; Mechanics; Mediating; Minerals; Modeling; Molecular; Mus; Muscle; Natural regeneration; Neonatal; Operative Surgical Procedures; Osteoblasts; Paralysed; Phenotype; Physiological; Population; Process; Proteoglycan; Publishing; Quality of life; Regulation; Relative (related person); Reporter; Research; Role; Rotator Cuff; Shoulder; Signal Pathway; Signal Transduction; Site; Solutions; Stem cells; Stress; Structure; System; Tendon structure; Time; Tissues; Transforming Growth Factor beta; Work; base; bone; bone healing; cell growth; clinically significant; fetal; healing; injured; ligament injury; mineralization; mouse model; novel; patient population; postnatal; prevent; progenitor; public health relevance; regenerative; repaired; scleraxis; sex; skeletal; smoothened signaling pathway

 DESCRIPTION (provided by applicant): Attachment of dissimilar materials is challenging due to stress concentrations that arise at their interface. The tendon-to-bone attachment site ("enthesis") solves this mechanical problem using a functionally graded transitional tissue that includes spatial gradients in structure, extracellular matrix composition, and cell phenotype. This strong and tough attachment system is formed during fetal and postnatal timepoints under the regulation of molecular and biophysical cues. Unfortunately, this unique structure is not recreated after surgical repair and healing, leading to remarkably high failure rates. Therefore, our goal is to gain an understanding of tendon enthesis development in order to motivate regenerative strategies for enthesis repair. Our overall hypothesis is that temporal and spatial regulation of biochemical (TGFß and Ihh) and biophysical (muscle force) cues are necessary to drive the development of a functional enthesis and for regeneration after injury. Our hypothesis is motivated by our recent work, which showed that embryonic tendon-to-bone attachment initiates from a distinct population of progenitor cells and postnatal enthesis maturation and mineralization is driven by Indian hedgehog signaling and muscle loading. It remains unclear, however, how these cell populations at the developing attachment regulate the formation of a mature enthesis. Therefore, Aim 1 will determine the lineage (or lineages) of the cells that compose the mature enthesis, starting at embryonic timepoints and progressing through skeletal maturity. Aim 2 will determine the molecular and mechanical regulation of the enthesis cell phenotype(s), focusing on TGFß for early developmental events and Ihh signaling for later mineralization events. In Aim 3, we will determine the role of enthesis cell lineages and molecular signaling for repair and regeneration of the injured enthesis, focusing on cells responsible for Ihh signaling at the enthesis. These aims will allow us to identify and characterize the cells that populate the enthesis and to uncover the molecular and biophysical sequence of events that is required for their differentiation. Results will have a direct impact on future cell- and growth factor-based regenerative strategies for tendon-to-bone repair.

 描述（通过应用程序提供）：由于其界面上出现的应力浓度而质疑不同材料的附件。肌腱到骨的附着位点（“衰减”）使用功能分级的过渡组织解决了这一机械问题，该组织包括结构，细胞外基质组成和细胞表型中的空间梯度。这 在分子和生物物理提示的调节下，在胎儿和产后时间点期间形成强大而坚韧的附着系统。不幸的是，这种独特的结构在手术修复和愈合后不会重新创建，导致失败率很高。因此，我们的目标是了解肌腱分节发育，以激励再生策略进行埃文修复。我们的总体假设是，必须暂时和空间调节生化（TGFß和IHH）以及生物物理（肌肉力）提示，以驱动功能性衰减的发展和受伤后的再生。我们的假设是由我们最近的工作激发的，这表明胚胎肌腱对骨的附着从不同的祖细胞群中启动，而产后的成熟和矿化是由印度刺猬信号传导和肌肉负荷驱动的。但是，尚不清楚这些细胞群体如何调节成熟源的形成。因此，AIM 1将确定构成成熟源的细胞的谱系（或谱系），从胚胎时间点开始，然后通过骨骼成熟度发展。 AIM 2将确定源细胞表型的分子和机械调节，重点介绍了早期发育事件的TGFß和IHH信号的后期矿化事件。在AIM 3中，我们将确定埃文细胞谱系和分子信号传导在损伤渗透的修复和再生中的作用，重点是负责Enthesis时IHH信号传导的细胞。这些目标将使我们能够识别和表征填充源头的细胞，并发现其分化所需的事件的分子和生物物理序列。结果将直接影响 未来的基于细胞和生长因子的再生策略，用于肌腱到骨修复。