NIH Director's Pioneer Award

在冬眠期间，某些哺乳动物可能会经历一种类似于可逆性暂停生命的生理状态，体温严重降低，核心体温(CBT)接近0摄氏度。在包括人类在内的非冬眠者中，这种程度的体温过低是致命的。众所周知，细胞在低氧条件下，由于新陈代谢减慢，在低温条件下存活时间更长，这一特征具有许多临床应用。由于器官衰竭的风险，低温的临床应用仅限于32-34oC的CBT。即使在这样的温度下，受控低温的有益效果也是显著的。实验小鼠不是冬眠者，但在热量限制下，它可以经历CBT为31摄氏度或更低的麻木(类似冬眠的)行为。像马达加斯加狐猴这样的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？-腺苷一磷酸(5？-AMP)是小鼠麻木行为的中介物。我们的研究表明，麻木行为与5？-AMP对血糖的调节有关，5-AMP是几种参与葡萄糖稳态的限速酶的重要变构调节剂。我们的发现提出了这样一种可能性，即非冬眠者也可以达到一种只有在冬眠哺乳动物中才能观察到的暂停生命状态。利用5？-AMP、环境温度和血糖等生理变量，可以诱导、维持和挽救小鼠的悬吊状态。颤抖，体温调节防御的信号被5？AMP阻挡，允许CBT迅速冷却到17摄氏度或更低，导致动物进入暂停生命。从长达10小时的暂停状态中恢复是自发的，但葡萄糖促进了恢复。我们的目标是将这项技术带入两个领域。1)探讨非冬眠哺乳动物暂停运动的生理极限。2)将实验室小鼠的发现扩展到进化链上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.