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

描述（由申请人提供）：小型哺乳动物和鸟类具有挑战性的生活方式：面对恶劣的环境， 经常是寒冷和食物短缺。一个非常高的特定质量的代谢率和无法储存大量的能量导致了一个非凡的生理/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不足或预期能量不足时，它们会变得迟钝，这是一种代谢率非常低的状态，可以保存储存的燃料以提高生存率。由于低代谢率，这些小型哺乳动物的体温下降到很大程度，在小鼠中低至20 º C，在真正的冬眠动物中更低。许多化合物，包括激素和代谢物，已被认为是麻木的介质。然而，这些化合物是否激活休眠诱导途径一直难以评估，因为大多数小鼠研究仅检查体温和/或可能的代谢率，尽管精心策划的生理/生化/分子变化很复杂。在该提议中，将测试以下假设：1）已知在小鼠中诱导体温过低和代谢减退的所有外周给药化合物不类似于“自然”发生的麻木2）集中给药的腺苷将诱导在多个（心血管、生物化学和分子）水平上类似于麻木的状态。这个重新提交的提案将采用从生理到分子的措施来评估这些假设。其中包括：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，和4）组织RNA表达。这一建议的一个主要优势是可用于评估低代谢状态的广泛测量。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。政府提供了一个非常有益的休假政策（每三年一次），在八年前建造了一个5000万美元的科学设施，为实验室和动物饲养提供了充足的空间，并为赠款计划提供了校内种子资金（比如这个）。我们在威廉姆斯学院的科学使命的一部分是本科生的曝光和成功的培训。学生经常承担大量的责任与研究项目和实验室环境往往需要在一个大气相媲美的研究生院的研究环境，学生与教师并肩工作，设计和进行复杂的研究。我的研究项目继续让本科生参与主流研究，让他们接触到复杂和当前的技术，采用综合生物学方法，测试特定的假设来推动研究。我提出的项目将提供一个很好的研究经验，为学生谁可能继续生产的科学事业。

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.