Mechanobiology of tendon development, growth, and maturation

肌腱发育、生长和成熟的力学生物学

基本信息

批准号：
10598565
负责人：
Alice H Huang
金额：
$ 18.02万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10598565
关键词：
3-Dimensional Address Adult Affect Benchmarking Biological Biological Response Modifier Therapy Biology Botulinum Toxins Cell Proliferation Cells Clinical Collagen Cytoplasm Data Set Development Embryo Engineering Failure Future Gel Gene Expression Profile Genetic Growth In Vitro Injury Knowledge Maintenance Measures Mechanics Mediating Modeling Molecular Morphology Mus Muscle Muscle Contraction Natural regeneration Nuclear Outcome Pain Paralysed Paraxial Mesoderm Pathway Analysis Pathway interactions Pattern Phenotype Population Proliferating Property Protocols documentation Regenerative pathway Regulation Role Serum Signal Transduction Structure Tendinopathy Tendon structure Testing Therapeutic Toxin Translating candidate identification defined contribution effective therapy embryonic stem cell functional restoration healing improved in vitro Model in vivo in vivo Model mechanical force mechanical signal mechanotransduction novel pharmacologic postnatal prevent rational design regenerative repaired response rho tendon development tendon rupture transcriptome sequencing

项目摘要

PROJECT SUMMARY With injury, tendon function is compromised due to poor healing and failure to regenerate native structure. There is an unmet clinical need for effective biologic therapies that improve tendon healing. However, this is limited by our incomplete understanding of basic tendon biology. In particular, the regulation of tendon cell fate, growth, and maturation during development remains poorly understood. One critical regulator of tendon development is muscle forces. During development, muscle forces are required for tendon patterning and growth. However, the mechanisms by which tendon cells translate mechanical cues into biological responses (mechanotransduction pathways), and how mechanical forces regulate specific aspects of development (cell proliferation, matrix elaboration, and functional maturation) is not understood. To address this knowledge gap, we established a 3D engineered tendon platform to model tendon mechanobiology during development, since muscle forces are not easily measured or controlled in vivo during developmental stages. We now propose to apply this engineered tendon platform to define the contributions of cells and matrix to tendon growth and test the requirement of two major mechanotransduction pathways (YAP/TAZ, MRTF/SRF). Our central premise is that muscle-mediated tendon growth and maturation during in vitro and in vivo development is mediated by YAP/TAZ and MRTF/SRF mechanotransduction. We further propose these pathways regulate distinct aspects and stages of tendon development.

项目摘要由于损伤，肌腱功能由于愈合差而无法再生天然结构而受到损害。对改善肌腱愈合的有效生物疗法的临床需求未满足。但是，这是受我们对基本肌腱生物学的不完全理解的限制。特别是，肌腱细胞命运的调节，增长和发展过程中的成熟仍然知之甚少。肌腱发育的一个关键调节剂是肌肉力。在发育过程中，肌肉力量是肌腱图案和生长所必需的。但是，肌腱细胞翻译的机制机械提示为生物学反应（机械转导途径），以及机械力如何调节发育的特定方面（细胞增殖，基质阐述和功能成熟）不是理解。为了解决这个知识差距，我们建立了一个3D工程肌腱平台来建模肌腱开发过程中的机械生物学，因为在体内不易在体内测量或控制肌肉力发展阶段。现在，我们建议应用此设计的肌腱平台来定义细胞和基质以肌腱生长并测试两种主要的机械转导途径的需求（YAP/TAZ，MRTF/SRF）。我们的主要前提是肌肉介导的肌腱生长和成熟体外和体内发育是由YAP/TAZ和MRTF/SRF机械传输介导的。我们进一步建议这些途径调节肌腱发育的不同方面和阶段。