NIH Director's Pioneer Award

NIH 院长先锋奖

• 批准号: 7916328
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7916328
• 关键词: Adenosine Monophosphate; Animals; Area; Award; Behavior; Body Temperature; Caloric Restriction; Cells; Enzymes; Glucose; Goals; Hibernation; Hour; Human; Hypoxia; Laboratory mice; Lemurs; Link; Mammals; Mediator of activation protein; Metabolism; Mus; Organ failure; Physiological; Primates; 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 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.

在冬眠期间，某些哺乳动物可以经历类似于可逆的悬浮动画的生理状态，具有严重的体温过低和接近0oC的核心体温（CBT）。在包括人类在内的非灭绝者中，这种体温过低程度是致命的。众所周知，由于新陈代谢放缓，缺氧下的细胞在低温条件下生存更长，这是许多临床应用的特征。由于有机衰竭的风险，低温的临床应用仅限于32-34oC的CBT。即使在这种温度下，受控体温过低的有益作用也很重要。实验室小鼠是一种非靠移灭剂，但在热量限制下，它可以以31oC或以下的CBT进行旋转（像冬眠的）行为。诸如马达加斯加狐猴之类的灵长类动物可以经历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）是小鼠torprapor行为的介体。我们的研究表明，Torpor行为与5？AMP的调节有关，这是对葡萄糖稳态涉及的几种限制速率限制酶的重要变构调节剂。我们的发现提出了一种可能仅在冬眠哺乳动物中观察到的悬浮动画状态的可能性。使用生理变量，5？ - 放大器，环境温度和葡萄糖，我们可以在悬挂动画中诱导，维持和拯救小鼠。颤抖的是，热调节防御的迹象被5？amp阻塞，使CBT快速冷却至17oC或以下，从而导致动物进入悬浮动画。从长达10个小时的悬浮动画状态恢复是自发的，但葡萄糖增强了。我们的目标是将这项技术带入两个领域。 1）探索非杀菌哺乳动物中悬浮动画的生理极限。 2）将发现从实验室小鼠扩展到沿进化链的其他非养生哺乳动物。

项目成果

AMP deaminase 3 deficiency enhanced 5'-AMP induction of hypometabolism.

• DOI: 10.1371/journal.pone.0075418
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Daniels IS;O Brien WG 3rd;Nath V;Zhao Z;Lee CC
• 通讯作者: Lee CC

Metabolite Profiling of 5'-AMP-Induced Hypometabolism.

• DOI: 10.1007/s11306-013-0552-7
• 发表时间: 2014-02-01
• 期刊: METABOLOMICS
• 影响因子: 3.6
• 作者: Zhao, Zhaoyang;Van Oort, Anita;Tao, Zhenyin;O'Brien, William G., III;Lee, Cheng Chi
• 通讯作者: Lee, Cheng Chi

New insights on the regulation of the adenine nucleotide pool of erythrocytes in mouse models.

• DOI: 10.1371/journal.pone.0180948
• 发表时间: 2017
• 期刊: PloS one
• 影响因子: 3.7
• 作者: O'Brien WG 3rd;Ling HS;Zhao Z;Lee CC
• 通讯作者: Lee CC