NIH Director's Pioneer Award

在冬眠期间，某些哺乳动物可以经历一种类似于可逆的生理状态， 假死，伴有严重的体温过低，核心体温（CBT）接近0摄氏度。在 对于包括人类在内的非冬眠动物来说，这种程度的低温是致命的。众所周知，细胞 在缺氧条件下生存更长的低温条件下，由于代谢减慢，一个功能， 许多临床应用。由于存在器官衰竭的风险，低温的临床应用受到限制 32-34摄氏度的CBT。即使在这样的温度下，控制低温的有益效果也是 显著实验室小鼠是一种非冬眠动物，但在热量限制下，它可以经历麻木 （冬眠样）行为，CBT为31摄氏度或以下。马达加斯加狐猴等灵长类动物 经历麻木，这表明这种行为的基本机制可能在人类身上保留下来。 我们最近发现内源性5？-腺苷酸（5？AMP）作为一种迟钝的媒介 小鼠的行为。我们的研究表明，迟钝行为与血糖的调节有关 5？AMP，葡萄糖参与的几种限速酶的重要变构调节剂 体内平衡我们的发现提出了一种可能性，即非冬眠动物也可以达到一种 只在冬眠的哺乳动物中观察到的假死现象。使用生理变量，5？- AMP、环境温度和葡萄糖等因素对小鼠悬浮模型的诱导、维持和挽救作用 动画颤抖是体温调节防御的一个标志，被5？AMP，允许快速冷却 将CBT的温度降至17摄氏度或以下，导致动物进入假死状态。采收 长达10小时的假死状态是自发的，但被葡萄糖增强。我们的目标是 将这项技术应用于两个领域。1)探讨假死的生理限度， 非冬眠哺乳动物2)将研究结果从实验室小鼠扩展到其他非冬眠小鼠 哺乳动物沿着进化链。

During hibernation, certain mammals can undergo a physiological state analogous to reversible suspended animation, with severe hypothermia and a core body temperature (CBT) close to 0 degrees C. In non-hibernators including the human, this degree of hypothermia is fatal. It is well established that cells under hypoxia survive longer in hypothermic conditions due to slowing of metabolism, a feature with many clinical applications. Due to the risk of organ failure, clinical application of hypothermia is limited to a CBT of 32-34 degrees C. Even at this temperature, the beneficial effect of controlled hypothermia is significant. The laboratory mouse is a non-hibernator but under caloric restriction it can undergo torpor (hibernating-like) behavior with a CBT of 31 degrees C or below. Primates such as Malagasy lemurs can undergo torpor, suggesting that the basic mechanism for such behavior may be preserved in humans. We have recently identified endogenous 5?-adenosine monophosphate (5?-AMP) as a mediator of torpor behavior in mice. Our studies revealed that torpor behavior is linked to the regulation of blood glucose by 5?-AMP, an important allosteric regulator of several rate-limiting enzymes involved in glucose homeostasis. Our finding raised the possibility that non-hibernators can also achieve a state of suspended animation observed only in hibernating mammals. Using the physiological variables, 5?- AMP, environmental temperature and glucose, we can induce, sustain and rescue mice in suspended animation. Shivering, a sign of thermo-regulatory defense, is blocked by 5?-AMP, allowing rapid cooling of CBT to 17 degrees C or below, causing the animal to enter suspended animation. Recovery from a suspended animation state of up to 10 hours is spontaneous but was enhanced by glucose. Our goal is to bring this technology into two areas. 1) To explore the physiological limits of suspended animation in non-hibernating mammals. 2) To extend findings from the laboratory mouse to other non-hibernating mammals along the evolutionary chain.