Matrix Metalloproteinases, Exercise, and Muscle Damage

描述(由申请人提供)： 候选人。候选人戴维·L·艾伦博士是一名研究助理，在生理学和分子生物学方面都有丰富的经验。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。他目前的职业目标是获得所有必要的研究和专业技能，以实现他的长期目标，即开发一个独立的、由外部资金资助的翻译研究项目，专注于动物和人类运动适应背后的分子机制。拟议的发展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)获得与建议的研究计划相关的新研究技能；(2)有组织的活动，包括出席期刊俱乐部、学术讨论会和全国和地方科学会议，以及与他的指导团队的定期互动。 环境主要赞助人道格拉斯·西尔斯博士是一位外部资助的科学家，有指导记录和二十年的人类运动研究经验；联合赞助商在研究计划的特定部分提供指导，包括肌肉生理学、分子生物学和遗传学。 研究。这一建议中要检验的假设如下：(1)基质金属蛋白酶(MMPs)的表达增加是离心性运动诱导的肌肉损伤和/或修复的中心组成部分；(2)由于基质金属蛋白酶基因启动子的多态导致的转录变化至少部分地导致了人体离心性运动后肌肉损伤和酸痛的变化。全身和肌肉中的基质金属蛋白酶水平将在一轮离心性运动后在人体内进行评估，并将与肌肉损伤和肌肉酸痛的指数相关联。此外，还将在小鼠身上进行药理学和遗传操作，以直接评估MMPs在肌肉损伤和修复中的因果作用。最后，受试者将接受已知功能性基质金属蛋白酶启动子基因多态的基因分型，这将与基质金属蛋白酶水平以及离心运动后的肌肉损伤和酸痛相关。

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.