The Role of Hydrogen Sulfide in the Hypoxia Tolerance of Hibernators

冬眠是哺乳动物的一种极端生理状态。小型冬眠动物，如地松鼠，通过陷入深度麻痹来度过冬天，在这种情况下，重要的生理速率和新陈代谢急剧下降，体温显著下降。在整个冬眠过程中，动物会被周期性的唤醒所打断，在这种唤醒过程中，动物会恢复到正常的夏季体温，并恢复身体功能。作为这种戏剧性循环的一部分，冬眠者自然会经历血流量减少和组织氧气供应耗尽（缺氧）。这种血液供应的中断和由此产生的缺氧对包括人类在内的非冬眠动物可能是致命的。通过研究冬眠的地松鼠如何在大脑等关键组织的低氧水平下生存，该项目扩展了我们对所有哺乳动物细胞能量产生策略的理解，并可能突出与大脑低氧条件相关的治疗新途径，如中风。具体来说，研究人员检查了一个信号通路，假设它能感知低氧条件并启动一种抑制细胞能量产生的反应。为了评估这种信号通路在自然冬眠动物中的功能，研究人员检查了13线地松鼠的代谢和缺氧耐受性，并比较了哺乳动物中关键基因的序列。该项目还促进了NSF培养新一代科学家和向公众提供科学发现的目标：该项目包括培训本科生和博士后研究人员，并通过社区健康改善中心和公共动物园进行公众宣传。小型冬眠动物的许多生理奥秘之一是它们对严重缺氧有明显的耐受性，这种耐受性发生在从深度麻木中重新唤醒时。这个项目的目标是确定支持冬眠地松鼠在正常缺氧敏感组织（如大脑）中耐缺氧的机制。在非耐缺氧物种如小鼠中，损伤性或致死性缺氧在脑中由气体递质硫化氢（H2S）的急性增加介导，其抑制电子传递链。该项目使用体内，体外和计算机模拟方法来研究假设，即深冬眠动物的脑细胞能够代谢H2S，这种先天能力是它们在严重缺氧事件中生存的基础。本研究解决了三个具体的目标，在大脑中的13线地松鼠（Ictidomys tridecemlineatus）。第一个目的是确定地松鼠吸入硫化氢的季节性反应，与大鼠相比。第二个目的是跟踪H2S的生产和代谢过程中缺氧暴露在孤立的线粒体和神经元。第三个也是最后一个目的是评估啮齿动物谱系内H2S产生和代谢的关键基因的选择压力。预计这些研究将促进我们对冬眠动物耐受脑缺氧的生化和生理适应的认识。

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.