NIH Director's Pioneer Award

NIH 院长先锋奖

• 批准号: 7292763
• 负责人: CHENG CHI LEE
• 金额: $ 74.25万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-28 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7292763
• 关键词: Adenosine Monophosphate; Animals; Area; Award; Behavior; Body Temperature; Caloric Restriction; Cells; Condition; Enzymes; Glucose; Goals; Hibernation; Hour; Human; Hypoxia; Laboratory mice; Lemurs; Link; Mammals; Mediator of activation protein; Metabolism; Mus; Organ failure; Personal Satisfaction; Physiological; Primates; Rate; Recovery; Risk; Shivering; Technology; Temperature; United States National Institutes of Health; animation; blood glucose regulation; clinical application; natural hypothermia

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.

在冬眠期间，某些哺乳动物可以经历类似于可逆的生理状态 悬浮动画，严重的体温过低和核心体温（CBT）接近0度。 包括人类在内的非临床者，这种体温过低的程度是致命的。众所周知，细胞 由于新陈代谢放缓而导致的低温状况下缺氧的生存时间更长，该特征的特征 许多临床应用。由于有器官衰竭的风险，体温过低的临床应用有限 至32-34度的CBT。即使在此温度下，受控体温过低的有益作用是 重要的。实验室鼠标是一种无源源，但在热量限制下，它可以经历torpor （类似冬眠的）行为，CBT为31度或以下。诸如马塔加斯加狐猴之类的灵长类动物可以 经历了Torpor，这表明这种行为的基本机制可以保存在人类中。 我们最近确定了内源性5？ - 腺苷单磷酸（5？amp）为Torpor的介体 小鼠的行为。我们的研究表明，Torpor行为与血糖的调节有关 到5？Amp，这是涉及葡萄糖的几种限速酶的重要变构调节剂 稳态。我们的发现提出了非解雇者也可以达到状态的可能性 仅在冬眠哺乳动物中观察到的暂停动画。使用生理变量，5？ - 放大器，环境温度和葡萄糖，我们可以诱导，维持和营救小鼠 动画片。颤抖是热调节防御的迹象，被5？amp阻塞，允许快速冷却 CBT至17度C或以下，导致动物进入悬浮动画。从a中恢复 悬浮的动画状态长达10个小时是自发的，但通过葡萄糖增强。我们的目标是 将这项技术带入两个领域。 1）探索悬浮动画的生理限制 非养哺乳动物。 2）将发现从实验室鼠标扩展到其他非解雇 沿进化链的哺乳动物。