CAREER: Remodeling and Damage of the Tendon Attachment During Postnatal Growth

这个教师早期职业发展（CAREER）补助金将控制肌腱的重塑及其在生长过程中与骨骼的连接。出生后的生长会对骨骼和肌肉产生独特的机械应力。随着骨骼肌变得更强壮，运动技能提高，肌腱和附件等结缔组织的柔韧性会降低。 肌腱及其附件将肌肉负荷传递给骨骼，因此其柔韧性的变化会影响骨骼负荷和运动。 肌肉卸载发生在出生后的生长。 这种卸载对肌腱附着的结构和功能具有不利影响。然而，肌肉超载对骨骼生长的影响仍然未知。 这是因为在快速生长和发育期间控制骨骼肌激活的能力具有挑战性。光遗传学已经成为一种强大的技术，用于空间和时间控制细胞，包括肌肉细胞。研究小组将使用光遗传学技术通过皮肤暴露蓝光来控制肌肉收缩。这将使他们能够在出生后生长的早期阶段精确地增加肌腱附着处的机械载荷。然后，他们将评估增加肌肉负荷对肌腱及其附着的影响。 具体来说，他们将测量生长和衰老过程中重塑和损伤的结果。这项工作的结果将为康复策略提供信息，以保持整个生命周期的肌肉骨骼健康。该奖项还将支持调查人员和地区教师之间的伙伴关系，以举办关于运动科学的研讨会，并由当地教师开发K-12课程单元。调查人员将与K12教师合作实施，评估和发布课程单元。 此外，研究人员还将通过向K12教师学习来改进自己的大学教学。在这个CAREER项目中，PI将使用体内光遗传学平台来测量由肌腱附着的重塑和损伤引起的结构、机械和分子变化，这些变化是由肌肉负荷的频率、幅度和持续时间依赖性变化驱动的，在出生后的生长（目标1）和成熟和老化的附件（目标2）。这项工作在本质上是变革性的，因为实验融合了跨学科的方法，使用来自神经科学（光遗传学），化学（胶原蛋白样肽），生命科学（激光捕获显微切割），生物力学（体内等长关节扭矩）和研究人员的专业知识（肌腱附着的机械生物学）的创新技术。该项目将评估诱导肌肉负荷对生长和老化过程中肌腱附着重塑和损伤的可测量结果的影响。这项研究的发现将填补我们对整个生命周期中附着机械生物学的基本理解的知识空白，并揭示与机械诱导的重塑和损伤相关的生物力学适应。该研究者将与当地K12教育工作者合作，继续指导博士、本科生和高中生进行工程研究，重点关注生长和衰老过程中组织重塑的机制。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

This Faculty Early Career Development (CAREER) grant will control the remodeling of tendon and its attachment to bone during growth. Postnatal growth places unique mechanical stresses on bones and muscles. As skeletal muscles get stronger and motor skills improve, the flexibility of connective tissues like tendons and attachments decreases. Tendons and their attachments transmit muscle loads to bone, so changes in their flexibility affect bone loading and movement. Muscle unloading occurs during postnatal growth. This unloading has detrimental effects on the structure and function of the tendon attachment. However, the effect that muscle overloading has on the growing skeleton remains unknown. This is because the ability to control skeletal muscle activation during periods of rapid growth and development is challenging. Optogenetics has emerged as a powerful technique for spatial and temporal control of cells, including muscle cells. The research group will use optogenetic techniques to control muscle contraction by the exposure of blue light through skin. This will allow them to precisely increase mechanical loading at the tendon attachment during the early stages of postnatal growth. They will then evaluate the effect of increased muscle loading on the tendons and their attachment. Specifically, they will measure outcomes of remodeling and damage during growth and aging. Findings from this work will inform rehabilitative strategies to maintain musculoskeletal health across the lifespan. This award will also support a partnership between the investigators and the regional teachers for the presentation of seminars on the Science of Movement and development of K-12 curriculum units by local area teachers. The investigators will work with K12 teachers to implement, assess, and publish curriculum units. Furthermore, the investigators will improve their own university teaching by learning from the K12 teachers.In this CAREER project, the PI will use an in vivo optogenetic platform to measure structural, mechanical, and molecular changes induced by remodeling and damage of the tendon attachment that are driven by frequency-, magnitude-, and duration-dependent changes in muscle loading, both during postnatal growth (Objective 1) and in the mature and aging attachment (Objective 2). This work is transformative in nature because the experiments merge together cross-disciplinary approaches using innovative techniques from neuroscience (optogenetics), chemistry (collagen like peptides), life sciences (laser capture microdissection), biomechanics (in vivo isometric joint torque), and the investigator’s expertise (mechanobiology of the tendon attachment). This program will evaluate the effect of inducible muscle loading on measurable outcomes of remodeling and damage of tendon attachments during growth and aging. Findings from this CAREER will fill a knowledge gap in our basic understanding of attachment mechanobiology across the lifespan and reveal biomechanical adaptations associated with mechanically-induced remodeling and damage. The investigator will engage with local K12 educators and continue to mentor PhD, undergraduate, and high school students in engineering research focused on the mechanisms of tissue remodeling during growth and aging.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.