Aging-associated dysregulation of the hypoxia pathway limits skeletal muscle regeneration

项目总结/摘要 本提案描述了Indranil博士的五年培训计划和职业发展计划 辛哈Sinha博士是国家老龄化研究所赞助的博士后个人国家 研究服务奖（F32）。他是一个研究和教育核心补助金的当前获奖者，通过 波士顿胡椒中心和国家老龄化研究所。他完成了整形外科的临床培训， 重建手术，并通过美国整形外科委员会认证。他现在是 在Amy Wagers博士的指导下开展研究和职业发展计划， 医学教授，哈佛医学院。Wagers博士是骨骼肌领域的资深研究员 再生，并有指导谁去成功的，独立的研究生涯的学员的历史。 世界著名的肌肉减少症研究人员Shalender Bhasin博士将提供额外的指导， 以及运动生理学专家劳里固特异博士。辛哈博士的职业发展计划包括 布里格姆妇女医院、乔斯林糖尿病中心和哈佛大学教育资源的利用 医学院布里格姆妇女医院也将提供职业发展支持 外科，主要研究者将在此期间担任主治医师 资金。辛哈博士为在同行评审期刊上发表自己的研究成果制定了一个明确的时间轴， 在国家会议上的演讲，在整形外科内建立老龄化兴趣小组，并计划 独立研究项目的发展和持续的研究资金。 Sinha博士有兴趣开发新的治疗策略，用于治疗与衰老相关的骨骼丢失。 肌肉再生他正在研究衰老改变缺氧通路信号传导的机制， 小鼠模型中骨骼肌再生潜力。他发现缺氧的两个关键因素 芳香烃受体核转位蛋白（ARNT）和血管内皮生长因子 血管内皮生长因子（VEGF）在骨骼肌中的表达在衰老过程中严重失调，并可能导致骨骼肌的丧失 再生潜力此外，使用转基因小鼠模型，他证明了肌肉 ARNT的特异性丢失概括了与衰老相关的骨骼肌再生减少。建筑 根据这些有趣的初步数据，本项目的中心目标是：（1）机械地定义 缺氧途径信号传导及其对衰老中肌肉再生的影响，（2）确定恢复 ARNT和VEGF信号转导以保持骨骼肌肌源性潜能，以及（3）确定肌肉是否 运动引起的肥大，已知需要骨骼肌再生和缺氧 在继发于ARNT丧失的老化中，

Project Summary/Abstract This proposal describes a five-year training program and career development plan for Dr. Indranil Sinha. Dr. Sinha is a prior trainee of a National Institute of Aging-sponsored Postdoctoral Individual National Research Service Award (F32). He is a current awardee of a Research and Education Core Grant through the Boston Pepper Center and the National Institute of Aging. He has completed clinical training in Plastic and Reconstructive Surgery and is board-certified through the American Board of Plastic Surgery. He is now embarking on a research and career development program under the mentorship of Amy Wagers, Ph.D., Professor of Medicine, Harvard Medical School. Dr. Wagers is an accomplished researcher in skeletal muscle regeneration and has a history of mentoring trainees who go on to successful, independent research careers. Additional mentoring will be provided by Dr. Shalender Bhasin, a world-renowned researcher on sarcopenia, and Dr. Laurie Goodyear, an expert on exercise physiology. Dr. Sinha's career development plan includes utilization of educational resources at Brigham and Women's Hospital, Joslin Diabetes Center, and Harvard Medical School. Career development support will also be provided by the Brigham and Women's Hospital Department of Surgery, where the principle investigator will serve as an attending physician during the period of funding. Dr. Sinha has developed a clear timeline for publication of his work in peer-reviewed journals, presentations at national meetings, establishment of an Aging Interest Group within Plastic Surgery, and plans for the development of independent research projects and continued research funding. Dr. Sinha is interested in developing novel treatment strategies for aging-associated loss of skeletal muscle regeneration. He is investigating mechanisms by which aging alters hypoxia pathway signaling and skeletal muscle regenerative potential in a murine model. He found that two key factors in the hypoxia pathway, aryl hydrocarbon receptor nuclear translocator (ARNT) and vascular endothelial growth factor (VEGF), are severely dysregulated in skeletal muscle in aging and may lead to a loss of skeletal muscle regenerative potential. Furthermore, using a genetically modified mouse model, he demonstrated that muscle specific loss of ARNT recapitulates diminished skeletal muscle regeneration as associated with aging. Building on these intriguing preliminary data, the central goals of this project are to (1) mechanistically define the role of hypoxia pathway signaling and its impact on muscle regeneration in aging, (2) identify interventions to restore ARNT and VEGF signaling to preserve skeletal muscle myogenic potential, and (3) determine whether muscle hypertrophy in response to exercise, which is known to require skeletal muscle regeneration and hypoxia signaling, is limited in aging secondary to loss of ARNT.