AREA: A1 - Hypothermia vs. Daily torpor: an integrative molecular /biochemical /

描述(申请人提供)：小型哺乳动物和鸟类有一个具有挑战性的生活方式：在恶劣的环境中保持中性或正能量平衡， 通常很冷，而且食物短缺。非常高的比质量代谢率和无法储存大量能量导致了一种非凡的生理/生化适应的进化。这种生理特征就是进入麻木状态的能力。当小型哺乳动物处于能量短缺或预期能量短缺时，它们会变得迟钝，这是一种代谢率非常低的状态，允许保存储存的燃料以提高存活率。由于代谢率低，这些小型哺乳动物的体温会很大程度上下降，小鼠的体温低至20摄氏度，而真正冬眠的动物体温更低。许多化合物，包括激素和代谢物，被认为是麻木的媒介。然而，这些化合物是否激活了麻木诱导通路一直很难评估，因为大多数在小鼠身上的研究只检查体温和/或代谢率，尽管精心安排的生理/生化/分子变化很复杂。在这项提议中，将检验以下假设：1)所有已知的外周给药导致小鼠体温过低和代谢低下的化合物并不类似于“自然”发生的昏迷2)腺苷集中给药将在多个水平(心血管、生化和分子)诱导类似麻木的状态。这份重新提交的提案将采用从生理到分子的各种方法来评估这些假说。这些包括：1)间接量热系统，2)基于遥测的血压/心率/体温检测系统，3)血液代谢物分析，以及4)组织RNA表达。这一建议的一个主要优点是可用于评估低代谢状态的广泛测量范围。威廉姆斯学院是一所小型文科学校，在教育和研究方面都取得了巨大的成功。这反映了学院对教师研究的真正支持性质。政府提供了一项极其有利的休假政策(每三年一次)，八年前建造了一座耗资5000万美元的科学设施，为实验室和动物住所提供了充足的空间，并为资助计划提供了校内种子资金(如这一项)。我们在威廉姆斯学院的科学使命的一部分是曝光和成功地培养本科生。学生经常对研究项目承担相当大的责任，实验室环境通常呈现出一种可与研究生院研究环境相媲美的氛围，在这种环境中，学生与教师并肩工作，设计和开展复杂的研究。我的研究计划继续让本科生参与主流研究，让他们以一种综合的生物学方法接触尖端和当前的技术，在这种方法中，测试特定的假设推动研究。我提议的项目将为那些可能继续从事富有成效的科学职业的学生提供极好的研究体验。

DESCRIPTION (provided by applicant): Small mammals and birds have a challenging lifestyle: maintaining a neutral or positive energy balance in the face of a harsh environment that is often cold and in short supply of food. A very high mass-specific metabolic rate and the inability to store a great deal of energy has led to the evolution of an extraordinary physiologica / biochemical adaptation. That physiological trait is the ability to enter torpor. When small mammals are in an energy deficit, or anticipate an energy deficit, they become torpid, a state of very low metabolic rate which allows for conservation of stored fuels for increased survival. As a consequence of the low metabolic rate, the body temperature of these small mammals declines to a large degree, as low as 20¿C in mice, and lower in true hibernators. Numerous compounds, including hormones and metabolites, have been suggested as mediators of torpor. However, whether these compounds activate torpor-inducing pathways has been difficult to assess as most studies in mice examine only body temperature and/or perhaps metabolic rate, despite the complexity of the well- orchestrated physiological / biochemical / molecular changes. In this proposal, the following hypotheses will be tested: 1) all peripherally-administered compounds known to induce hypothermia and hypometabolism in mice do not resemble "naturally" occurring torpor 2) adenosine administered centrally will induce a state that resembles torpor at multiple (cardiovascular, biochemical, and molecular) levels. This resubmitted proposal will employ measures that range from physiological to molecular to assess these hypotheses. These include: 1) an indirect calorimetry system, 2) a telemetry- based blood pressure / heart rate / body temperature detection system, 3) blood metabolite analysis, and 4) tissue RNA expression. One major strength of this proposal is the wide spectrum of measurements available for assessment of hypometabolic states. Williams College is a small liberal arts school that has had wonderful success excelling in both education and research endeavors. This reflects the truly supportive nature of the college towards faculty research. The administration offers an extremely beneficial sabbatical policy (every three years), built a $50 million science facility eight years ago, provides ample space for labs and animal housing, and offers intramural seed money for grant initiatives (like this one). Part of our mission in the sciences at Williams College is the exposure and successful training of undergraduates. Students regularly assume a significant amount of responsibility with research projects and the laboratory environment often takes on an atmosphere comparable to a graduate school research environment where students are working side-by-side with the faculty to design and conduct sophisticated research. My research program continues to involve undergraduates in mainstream research, exposing them to sophisticated and current technology in an integrative biology approach where testing specific hypotheses drive the research. My proposed project would provide an excellent research experience for students who are likely to go on to productive scientific careers.