Mammalian Hibernation Research- A Path Towards a Center for Transformative Research in Metabolism

项目摘要--总体 本申请是对PAR-16-415，生物医学研究卓越中心(COBRE)(第20页)的响应。 拟议的一期中心(P1C)建立在坚实的基础上，并长期致力于冬眠 阿拉斯加大学北极生物研究所(IAB)的研究。P1C的目标是使用 IAB的专业知识，特别是私人侦探凯利·德鲁博士为建立和加强阿拉斯加大学的 冬眠研究基础设施。该计划涉及指导三名调查人员的职业发展， 在研究方面经验丰富，但尚未从NIH获得R01，并指导 新的研究人员目前对冬眠研究表现出了兴趣。长期目标，可能超出 P1C的生命，是将所学到的关于生理变化的潜在机制应用于 冬眠到与新陈代谢和代谢性疾病相关的尚未解决的问题，如废用肌肉 人类的萎缩、骨质疏松症、肥胖症、2型糖尿病和心血管疾病。该中心将支持 有经验的科学家和刚开始研究的科学家的研究和职业发展。 该中心将专注于从基础研究到翻译研究的所有阶段。通过定义翻译 冬眠中的发现之路，P1C将有助于调查人员的职业发展。 强有力的行政和科学领导将通过以下四个方面实现P1C的目标 特定目标(SA)：SA1。建立组织结构和研究基础设施，以支持和 促进一个多学科框架，以确定冬眠哺乳动物的代谢适应机制。 SA 2.加强P1C项目主管和新调查员的职业生涯，通过 P1C，以使他们能够成功地竞争NIH个人研究拨款。SA3.支持研究 旨在加深对生理、遗传和肠道微生物的了解的项目和试点项目 冬眠的机制以及这些机制如何在治疗废用性肌肉萎缩或 石棺减少症。支持与中心主题相关的临床研究项目。季节性冬眠者 可以说，在新陈代谢、食欲、饮食、身体成分和 任何哺乳动物在其年度周期中的体温。这些极端现象提供了对监管机构的洞察 机制，以及在传统临床前模型中不太明显的可用药靶点。这个P1C 重点介绍与骨骼蛋白质合成和保存有关的遗传和肠道微生物机制 冬眠哺乳动物长时间停用和禁食期间的肌肉。一旦完成，新的调查人员将 具备识别和转化治疗方法的能力，以促进合成代谢敏感性和肌肉质量的保存 和力量。这些发现有可能通过以下方式每年在美国节省10亿美元的医疗成本 降低老年人和行动不便的成年人的残疾、住院和死亡风险。

Project Summary - Overall This application is in response to PAR-16-415, Centers of Biomedical Research Excellence (COBRE) (P20). The proposed phase 1 center (P1C) is built on a strong foundation and long-term commitment to hibernation research at the University of Alaska's Institute of Arctic Biology (IAB). The objective of the P1C is to use the expertise at IAB, in particular that of Dr. Kelly Drew, the PI, to build and strengthen the University of Alaska's hibernation research infrastructure. The plan involves guiding the career development of three investigators, experienced in research, but who have yet to receive R01s from NIH, and to guide the career development of new investigators currently showing an interest in hibernation research. The long-term goal, likely beyond the life of the P1C, is to apply what is learned about the mechanisms underlying the physiological changes in hibernation to as yet unresolved issues relevant to metabolism and metabolic diseases such as disuse muscle atrophy, sarcopenia, obesity, type 2 diabetes and cardiovascular diseases in humans. The center will support the research and career development of both experienced scientists and those getting their start in research. The center will have a focus on all stages of research from basic through translational. By defining translational paths for discoveries in hibernation, the P1C will contribute to the career development of the investigators. Strong administrative and scientific leadership will accomplish the goals of this P1C through the following four Specific Aims (SA): SA1. Establish an organizational structure and research infrastructure that will support and promote a multidisciplinary framework to define mechanisms of metabolic adaptations in hibernating mammals. SA 2. Enhance the careers of P1C project PIs as well as new investigators leading pilot projects through the P1C in order to allow them to compete successfully for NIH individual research grants. SA3. Support research projects and pilot projects aimed at developing an understanding of physiological, genetic and gut microbial mechanisms in hibernation and how these mechanisms may play a role in treating disuse muscle atrophy or sarcopenia. SA 4. Support clinical research projects related to the theme of the center. Seasonal hibernators arguably display the most dramatic natural alterations in metabolism, appetite, diet, body composition and body temperature of any mammal across their annual cycle. Such extremes offer insight into regulatory mechanisms, and druggable targets that would be less obvious in traditional pre-clinical models. This P1C focuses on genetic and gut microbial mechanisms related to protein synthesis and preservation of skeletal muscle during prolonged disuse and fasting in hibernating mammals. Once completed new investigators will be equipped to identify and translate treatments to promote anabolic sensitivity and preservation of muscle mass and strength. Such discoveries have the potential to save $1 billion per year in health-care costs in the US by reducing risk for disability, hospitalization, and death in older and mobility impaired adults.