NIH Director's Pioneer Award

University Of Texas Hlth Sci Ctr Houston, Houston TX

Investigators

Linked publications & trials

Abstract

During hibernation, certain mammals can undergo a physiological state analogous to reversible[unreadable] suspended animation, with severe hypothermia and a core body temperature (CBT) close to 0 degrees C. In[unreadable] non-hibernators including the human, this degree of hypothermia is fatal. It is well established that cells[unreadable] under hypoxia survive longer in hypothermic conditions due to slowing of metabolism, a feature with[unreadable] many clinical applications. Due to the risk of organ failure, clinical application of hypothermia is limited[unreadable] to a CBT of 32-34 degrees C. Even at this temperature, the beneficial effect of controlled hypothermia is[unreadable] significant. The laboratory mouse is a non-hibernator but under caloric restriction it can undergo torpor[unreadable] (hibernating-like) behavior with a CBT of 31 degrees C or below. Primates such as Malagasy lemurs can[unreadable] undergo torpor, suggesting that the basic mechanism for such behavior may be preserved in humans.[unreadable] We have recently identified endogenous 5?-adenosine monophosphate (5?-AMP) as a mediator of torpor[unreadable] behavior in mice. Our studies revealed that torpor behavior is linked to the regulation of blood glucose[unreadable] by 5?-AMP, an important allosteric regulator of several rate-limiting enzymes involved in glucose[unreadable] homeostasis. Our finding raised the possibility that non-hibernators can also achieve a state of[unreadable] suspended animation observed only in hibernating mammals. Using the physiological variables, 5?-[unreadable] AMP, environmental temperature and glucose, we can induce, sustain and rescue mice in suspended[unreadable] animation. Shivering, a sign of thermo-regulatory defense, is blocked by 5?-AMP, allowing rapid cooling[unreadable] of CBT to 17 degrees C or below, causing the animal to enter suspended animation. Recovery from a[unreadable] suspended animation state of up to 10 hours is spontaneous but was enhanced by glucose. Our goal is[unreadable] to bring this technology into two areas. 1) To explore the physiological limits of suspended animation in[unreadable] non-hibernating mammals. 2) To extend findings from the laboratory mouse to other non-hibernating[unreadable] mammals along the evolutionary chain.