Modifying muscle remodeling following Achilles tendon ruptures

项目摘要 候选人：巴克斯特博士获得了运动学博士学位和骨科生物力学博士后培训。 他的长期目标是成为一名独立的研究人员，专注于改善患者的预后， 肌腱损伤通过跨学科的研究框架（1）使用小动物模型，以确定 控制肌肉肌腱愈合和功能的机制，以便（2）优化测试的治疗方法 在对照临床试验中。因此，这项建议的目的是让他获得必要的培训， 小动物模型，超声成像，肌肉生理学和实验室技术来定义 控制有利于运动功能的肌肉-肌腱重塑的生物力学机制。 指导委员会和培训计划：Soslowsky博士将担任主要导师，并提供结构化的 指导小动物模型，实验室技术，并提供职业发展培训。Drs. Sehgal，Khurana，Farber和Thelen将担任共同导师，并提供超声方面的实践培训 成像、肌肉生理学、外科技术和临床翻译，以及非侵入性负荷测量， 分别巴克斯特博士还将定期参加研讨会，讲习班和课程，重点是 生物统计学，生物工程，医学成像，肌肉生理学，拨款写作和职业发展; 每年出席两次全国性会议;继续进行负责任的研究教育。 环境：宾夕法尼亚大学是麦凯骨科研究实验室和宾夕法尼亚大学的所在地。 肌肉骨骼疾病中心（PCMD），一个17,500平方英尺的研究空间，为拟议的 培训和研究计划。PCMD和托管几个NIH支持的核心服务，重点是 肌肉骨骼研究，包括组织学、生物力学和成像。PCMD和Penn主机 医学成像、肌肉生理学、生物工程和专业发展方面的每周/每月研讨会。 研究：这项拟议的工作将挑战目前的范式，即跟腱断裂是孤立的 肌腱损伤核心假设是肌肉-肌腱张力启动了肌肉的前向反馈回路 愈合过程中的重建和肌腱伸长。为了验证这一新的假设，将完成3个目标。目的 1将建立跟腱断裂和手术修复对肌肉成分和肌腱的影响 肌腱愈合过程中的生物力学目的2将明确肌腱张力对肌肉重塑的作用 使用临床相关的足部负荷装置和渐进式拉伸。目标3将修改肌腱伸长 使用非损伤性肌肉-肌腱刺激肌肉重塑治疗跟腱断裂 拉伸协议。测试这些目标将为后续R 01生成关键的初步数据， 临床相关的负荷模式，减轻有害的肌肉重塑和保留功能。 机构对候选人的承诺：巴克斯特博士已获得启动资金、实验室空间和 研究人员，并已被批准晋升为研究员轨道由他的部门。

PROJECT SUMMARY Candidate: Dr. Baxter received his PhD in kinesiology and post-doctoral training in orthopaedic biomechanics. His long-term goal is to become an independent researcher focused on improving patient outcomes following tendon injuries through an interdisciplinary research framework (1) using small animal models to identify mechanisms that govern muscle-tendon healing and function in order to (2) optimize treatments that are tested in controlled clinical trials. Therefore, the objective of this proposal is for him to acquire the training necessary in small animal models, ultrasound imaging, muscle physiology, and laboratory techniques to define the biomechanical mechanisms that govern muscle-tendon remodeling that are advantageous to locomotor function. Mentoring Committee and Training Plan: Dr. Soslowsky, will serve as primary mentor and provide structured mentoring in of small animal models, laboratory techniques, and provide career development training. Drs. Sehgal, Khurana, Farber, and Thelen will serve as co-mentors and provide hands-on training in ultrasound imaging, muscle physiology, surgical techniques and clinical translation, and non-invasive load measurement, respectively. Dr. Baxter will also participate regularly in seminars, workshops, and coursework focused on biostatistics, bioengineering, medical imaging, muscle physiology, grant writing, and career development; present at two national conferences each year; and continuing education on responsible conduct of research. Environment: The University of Pennsylvania is home to the McKay Orthopaedic Research Laboratory and Penn Center for Musculoskeletal Disorders (PCMD), a 17,500 ft2 research space that is well-equipped for the proposed training and research plan. The PCMD and hosts several NIH supported core services focused on musculoskeletal research, which include histology, biomechanics, and imaging. Both the PCMD and Penn host weekly/monthly seminars in medical imaging, muscle physiology, bioengineering, and professional development. Research: This proposed work will challenge the current paradigm that Achilles tendon ruptures are isolated tendon injuries. The central hypothesis is that muscle-tendon tension initiates a forward-feedback loop of muscle remodeling and tendon elongation during healing. To test this novel hypothesis, 3 aims will be completed. Aim 1 will establish the effects of Achilles tendon rupture and surgical repair on muscle composition and tendon biomechanics throughout tendon healing. Aim 2 will define the role of tendon tension on muscle remodeling using a clinically-relevant foot loading device and progressive stretching. Aim 3 will modify tendon elongation following Achilles tendon rupture by stimulating muscle remodeling using non-damaging muscle-tendon stretching protocols. Testing these aims will generate critical preliminary data for a follow-up R01 that optimizes clinically-relevant loading paradigms that mitigate detrimental muscle remodeling and preserves function. Institutional Commitment to Candidate: Dr. Baxter has been provided start-up funds, laboratory space, and research personnel and has been approved to be promoted to the research faculty track by his department.