NIH Director's Pioneer Award

在冬眠期间，某些哺乳动物可以经历类似于可逆假死的生理状态，严重的体温过低，核心体温（CBT）接近0 ℃。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，由于代谢减慢，缺氧条件下的细胞在低温条件下存活更长时间，这是具有许多临床应用的特征。由于器官衰竭的风险，低温的临床应用仅限于32- 34 ℃的CBT。即使在这个温度下，控制性低温的有益效果也是显著的。实验室小鼠是一种非冬眠动物，但在热量限制下，它可以在31 ℃或更低的CBT下进行麻木（冬眠样）行为。马达加斯加狐猴等灵长类动物可以经历麻木，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）作为小鼠麻痹行为的介质。我们的研究表明，迟钝行为与5？- AMP是参与葡萄糖稳态的几种限速酶的重要变构调节剂。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有在冬眠哺乳动物中才能观察到的假死状态。使用生理变量，5？- AMP、环境温度和葡萄糖等因素对小鼠假死有诱导、维持和抢救作用。颤抖，体温调节防御的标志被5？AMP，使CBT迅速冷却至17 ℃或以下，使动物进入假死状态。从长达10小时的假死状态恢复是自发的，但葡萄糖可增强恢复。我们的目标是将这项技术引入两个领域。1)探讨非冬眠哺乳动物假死的生理限度。2)将研究结果从实验室小鼠扩展到进化链沿着的其他非冬眠哺乳动物。

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 0oC. 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 32-34oC. 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 31oC 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 17oC 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.