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，某些哺乳动物会经历类似于可逆假死的生理状态，体温严重降低，核心体温 (CBT) 接近 0oC。对于包括人类在内的非冬眠者来说，这种程度的体温过低是致命的。众所周知，由于新陈代谢减慢，缺氧下的细胞在低温条件下存活时间更长，这是许多临床应用的一个特征。由于存在器官衰竭的风险，低温临床应用仅限于CBT 32-34oC。即使在这个温度下，控制低温的有益效果也是显着的。实验室小鼠不冬眠，但在热量限制下，它会出现麻木（类冬眠）行为，CBT 为 31oC 或以下。马达加斯加狐猴等灵长类动物可能会出现麻木状态，这表明人类可能保留了这种行为的基本机制。我们最近发现内源性 5?-单磷酸腺苷 (5?-AMP) 是小鼠麻木行为的调节剂。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。我们的发现提出了一种可能性，即非冬眠动物也可以达到仅在冬眠哺乳动物中观察到的假死状态。利用生理变量、5?-AMP、环境温度和葡萄糖，我们可以诱导、维持和拯救处于假死状态的小鼠。颤抖是体温调节防御的标志，被 5?-AMP 阻断，使 CBT 迅速冷却至 17°C 或以下，导致动物进入假死状态。从长达 10 小时的假死状态中恢复是自发的，但通过葡萄糖可以增强。我们的目标是将这项技术引入两个领域。 1）探索非冬眠哺乳动物假死的生理极限。 2) 将实验室小鼠的研究结果扩展到进化链上的其他非冬眠哺乳动物。

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