Mechanisms underlying tendon regeneration and attachment site pattern restoration

L珍娜·加洛韦项目总结 肌腱在形成肌肉骨骼组织之间建立了必要的联系， 使协调运动成为可能。对人类社会发展和模式的破坏 肌肉骨骼系统可导致骨骼畸形或痉挛，先天性 导致关节运动收缩的异常。成年人的肌肉骨骼 受伤在活跃的个人和老龄化的人口中很常见。肌腱损伤，在 尤其是，由于愈合缓慢而有限，可能会造成严重的行动不便、疼痛、 和生活质量问题。对指导肌腱的分子途径有全面的了解 发育和再生将对我们理解糖尿病的病因产生广泛的影响。 先天性缺陷以及再生医学治疗肌腱损伤的方法。这 该提案旨在利用斑马鱼来了解肌腱细胞的潜在机制 附着点模式的重建和再生。我们之前的研究已经 研究表明，斑马鱼和哺乳动物的肌腱在基因表达、发育 调控和超微结构特性，使它们成为研究的极佳遗传系统 肌腱生物学。我们还发现斑马鱼有很强的再生肌腱组织的能力 与成年哺乳动物不同。在这项新工作的基础上，我们建议使用基因细胞消融 解剖肌腱再生的细胞和分子机制的模型 依附模式的恢复。我们将确定新再生肌腱的来源 使用细胞增殖分析、遗传谱系追踪和实时成像。骨形态发生蛋白的检测 反应元件转基因斑马鱼和功能分析表明BMP信号在 特定附着部位的再生。此外，一个高通量的化学筛查发现 具有肌腱促进活性的化合物，其靶标可能与BMP途径相交。 利用化学和遗传功能分析，我们将剖析BMP信号在肌腱中的作用 再生和重新建立特定的附着部位。我们还将测试是否 化学物质和它们所针对的途径可以通过它们的 与BMP途径的潜在交叉点。我们的方案将新颖的工具与实时成像相结合 和功能研究，这将为肌腱细胞提供前所未有的可视化 再生过程中的行为。我们相信这些研究将增加对肌腱的重要洞察。 发育和再生，这可能会影响我们对先天性疾病和 再生医学对肌腱损伤的治疗方法。

Galloway, Jenna L Project Summary Tendons make essential connections between the forming musculoskeletal tissues, enabling coordinated movement. Disruption to the development and patterning of the musculoskeletal system can result in skeletal malformations or contractures, a congenital abnormality that results in constriction in the movement of joints. In adults, musculoskeletal injuries are common among active individuals and the aging population. Tendon injuries, in particular, are complicated by a slow and limited healing, which can pose significant mobility, pain, and quality of life issues. Comprehensive knowledge of the molecular pathways that guide tendon development and regeneration would have broad impact in our understanding of the etiology of congenital defects as well as in regenerative medicine approaches to tendon injuries. This proposal aims to use the zebrafish to understand the mechanisms underlying tendon cell regeneration and the re-establishment of attachment site pattern. Our previous studies have shown that zebrafish and mammalian tendons are similar in gene expression, developmental regulation, and ultrastructural properties, making them an excellent genetic system for studying tendon biology. We also find zebrafish have robust abilities to regenerate their tendon tissue unlike adult mammals. Building from this novel work, we propose to use a genetic cell ablation model to dissect the cellular and molecular mechanisms underlying tendon regeneration and the restoration of the attachment pattern. We will identify the source of the newly regenerating tendon cells using cell proliferation assays, genetic lineage tracing, and live imaging. Examination of BMP Responsive Element transgenic zebrafish and functional analysis indicate BMP signaling in the regeneration of specific attachment sites. In addition, a high-throughput chemical screen identified compounds with tendon promoting activities and whose targets may intersect the BMP pathway. Using chemical and genetic functional assays, we will dissect the role of BMP signaling in tendon regeneration and the re-establishment of a specific attachment site. We will also test if the chemicals and the pathways they target can augment the regenerative response through their potential intersection with the BMP pathway. Our proposal combines novel tools with live imaging and functional studies and together, this will provide unprecedented visualization of tendon cell behaviors during regeneration. We believe these studies will add crucial insight into tendon development and regeneration, which could impact our understanding of congenital disorders and regenerative medicine approaches to tendon injuries.