Matrix Metalloproteinases, Exercise, and Muscle Damage

描述（由申请人提供）： 候选人候选人大卫L.艾伦博士，是一位在生理学和分子生物学方面具有丰富经验研究人员。艾伦博士过去和现在的研究主要集中在动物骨骼肌适应的细胞和分子机制上。他的近期职业目标是获得实现他的长期目标所需的任何和所有研究和专业技能，该目标是开发一个独立的，由校外资助的转化研究计划，重点是动物和人类运动适应的分子机制。拟定的开发计划将为艾伦博士提供实现这一目标所需的额外经验和培训。 职业发展计划。艾伦博士建议的培训活动包括：（1）获得与拟议研究计划相关的新研究技能;（2）结构化活动，包括参加期刊俱乐部，座谈会，国家和地方科学会议，并与他的指导团队定期互动。 环境主要发起人道格拉斯·西尔斯博士是一位获得校外资助的科学家，他在人类运动研究方面有着20年的指导经验;共同发起人在研究计划的特定组成部分提供指导，包括肌肉生理学、分子生物学和遗传学。 Research.本研究提出的假设如下：（1）基质金属蛋白酶（MMPs）表达增加是离心运动诱导的肌肉损伤和/或修复的核心组成部分;（2）MMP基因启动子多态性导致的转录变化至少是离心运动后人类肌肉损伤和疼痛变化的一部分。将在一次离心运动后在人类受试者中评估全身和肌肉MMP水平，并将其与肌肉损伤和肌肉酸痛的指数相关联。此外，将在小鼠中使用药理学和遗传操作来直接评估MMPs在肌肉损伤和修复中的因果作用。最后，将对受试者进行已知功能性MMP启动子多态性的基因分型，这将与MMP水平和离心运动后的肌肉损伤和疼痛相关。

DESCRIPTION (provided by applicant): Candidate. The candidate, David L. Allen, Ph.D., is a research associate with extensive experience in both physiology and molecular biology. Dr. Allen's past and current research has focused on the cellular and molecular mechanisms underlying skeletal muscle adaptation in animals. His immediate career goal is to acquire any and all research and professional skills necessary for achieving his long-term goal of developing an independent, extramurally-funded translational research program focusing on the molecular mechanisms underlying exercise adaptation in both animals and humans. The proposed development plan will provide Dr. Allen with the additional experience and training necessary to achieve this goal. Career Development plan. Dr. Allen's proposed training activities consist of: (1) acquiring new research skills associated with the proposed research plan; (2) structured activities including attendance and presentation at journal clubs, colloquia, and national and local scientific meetings, and regular interactions with his mentoring team. Environment. The primary sponsor, Dr. Douglas Seals, is an extramurally funded scientist with a record of mentoring and two decades of experience in human exercise research; the co-sponsors provide guidance in specific components of the research plan, including muscle physiology, molecular biology, and genetics. Research. The hypotheses to be tested in this proposal are the following: (1) increased expression of matrix metalloproteinases (MMPs) is a central component of eccentric exercise-induced muscle damage and/or repair; (2) variations in transcription as a consequence of promoter polymorphisms in the MMP genes are responsible for at least part of the variation in muscle damage and soreness in humans following eccentric exercise. Systemic and muscle MMP levels will be assessed in human subjects following a bout of eccentric exercise and will be correlated with indices of muscle damage and muscle soreness. In addition, pharmacological and genetic manipulations will be used in mice to directly evaluate the causal role of MMPs in muscle damage and repair. Finally, subjects will be genotyped for known functional MMP promoter polymorphisms, which will be correlated with MMP levels and muscle damage and soreness following eccentric exercise.