The Role of Hydrogen Sulfide in the Hypoxia Tolerance of Hibernators

点击翻译按钮获取中文摘要

Hibernation is an extreme physiological condition among mammals. Small hibernators, such as ground squirrels, survive the winter by falling into deep bouts of torpor, in which vital physiological rates and metabolism are reduced dramatically and body temperature drops significantly. Torpor is punctuated throughout hibernation by periodic arousals, in which animals re-warm to normal summer body temperatures, and restore body functions. As part of this dramatic cycling, hibernators naturally experience reduced blood flow and depleted oxygen supply (hypoxia) to tissues. Such disruptions in blood supply and resulting hypoxia can be lethal to non-hibernators, including humans. By examining how hibernating ground squirrels survive low oxygen levels in critical tissues such as the brain, this project expands our understanding of strategies for cellular energy production in all mammals, and may highlight new avenues for therapies associated with low oxygen conditions in the brain, such as stroke. Specifically, the investigators examine a signaling pathway hypothesized to sense low oxygen conditions and initiate a response that suppresses cellular energy production. To evaluate the function of this signaling pathway in a natural hibernator, the investigators examine metabolism and hypoxia tolerance in 13-lined ground squirrels, and compare the sequences of key genes among mammals. The project also furthers the NSF goals of training new generations of scientists and making scientific discoveries available to the general public: the project includes training of undergraduate students and a postdoctoral researcher, and public outreach via a center for community health improvement and a public zoo. One of the many physiological mysteries of small-bodied hibernators is their marked tolerance to severe hypoxia, which occurs during rewarming arousal from deep torpor bouts. The goal of this project is to identify mechanisms that support hypoxia tolerance of hibernating ground squirrels in normally hypoxia-sensitive tissues such as the brain. In non-hypoxia tolerant species like mice, damaging or lethal hypoxia is mediated in the brain by an acute increase in the gasotransmitter hydrogen sulfide (H2S), which inhibits the electron transport chain. This project uses in vivo, in vitro and in silico approaches to examine the hypothesis that the brain cells of deep hibernators are able to metabolize H2S, and that this innate ability underlies their survival of severe hypoxic events. This study addresses three specific objectives in the brain of 13-lined ground squirrels (Ictidomys tridecemlineatus). The first aims serves to determine the seasonal responsiveness of ground squirrels to inhaled H2S, in comparison to rats. The second aim serves to track H2S production and metabolism during hypoxia exposure in isolated mitochondria and neurons. The third and last aim serves to evaluate selective pressures on the key genes of H2S production and metabolism within the rodent lineage. It is expected that the proposed studies will advance our knowledge of the biochemical and physiological adaptations that allow hibernators to tolerate cerebral hypoxia.