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

项目摘要/摘要 该提案描述了Indranil博士的五年培训计划和职业发展计划 辛哈。辛哈博士是国家老龄研究所资助的博士后个人国立大学的高级实习生 研究服务奖(F32)。他现为研究及教育核心资助金获得者。 波士顿胡椒中心和国家老龄研究所。他已经完成了整形和临床培训 重建外科，并通过美国整形外科委员会的董事会认证。他现在是 在艾米·韦杰斯博士的指导下开始研究和职业发展计划， 哈佛医学院医学教授。韦杰斯博士是一位在骨骼肌领域颇有成就的研究员。 并有指导学员走向成功的独立研究职业生涯的历史。 其他指导将由世界著名的石棺减少症研究人员沙伦德·巴辛博士提供。 以及运动生理学专家劳里·古德伊尔博士。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的教育资源利用情况 医学院。布里格姆妇女医院还将提供职业发展支助。 外科，在此期间，首席调查员将担任主治医生 资金的问题。辛哈博士制定了在同行评议期刊上发表他的研究成果的明确时间表， 在全国会议上的介绍，在整形外科领域内成立老龄问题小组，以及计划 用于独立研究项目的开发和继续研究的资金。 辛哈博士对开发与衰老相关的骨骼丢失的新治疗策略感兴趣 肌肉再生。他正在研究衰老改变缺氧信号通路和 小鼠模型中的骨骼肌再生潜力。他发现低氧的两个关键因素 芳烃受体核转运体与血管内皮生长因子途径 (血管内皮生长因子)，在骨骼肌衰老过程中严重失调，并可能导致骨骼肌丧失 再生潜力。此外，使用转基因小鼠模型，他展示了肌肉 ARNT的特异性丢失重述了骨骼肌再生与衰老相关的减少。建房 根据这些耐人寻味的初步数据，该项目的中心目标是(1)机械地定义 缺氧信号通路及其对衰老肌肉再生的影响，(2)确定恢复的干预措施 ARNT和血管内皮生长因子信号转导以保护骨骼肌的生肌潜能，以及(3)决定肌肉是否 运动引起的肥大，已知需要骨骼肌再生和低氧 信号转导，仅限于继发于ARNT缺失的衰老。

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.