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，通过陷入深度冬眠来度过冬天，在这种状态下，重要的生理速率和新陈代谢急剧降低，体温显著下降。冬眠期间，冬眠动物会被周期性的唤醒打断，在这个过程中，动物会恢复到正常的夏季体温，恢复身体机能。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缺氧。这种血液供应中断和由此导致的缺氧对包括人类在内的非冬眠动物来说是致命的。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存活下来，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，并可能为与大脑低氧条件（如中风）相关的治疗提供新的途径。具体来说，研究人员研究了一种信号通路，假设它能感知低氧条件，并启动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行地松鼠的新陈代谢和缺氧耐受性，并比较了哺乳动物中关键基因的序列。该项目还促进了国家科学基金会培养新一代科学家和使科学发现向公众开放的目标：该项目包括培养本科生和博士后研究员，并通过社区卫生改善中心和公共动物园进行公众宣传。小体冬眠动物的许多生理奥秘之一是它们对严重缺氧的显著耐受性，这种耐受性发生在从深度麻木中苏醒时。该项目的目标是确定冬眠地松鼠在正常缺氧敏感组织（如大脑）中耐受缺氧的机制。在小鼠等非耐缺氧物种中，大脑中有害或致命的缺氧是由气体递质硫化氢（H2S）的急性增加介导的，硫化氢会抑制电子传递链。该项目采用体内、体外和计算机方法来检验深冬眠动物的脑细胞能够代谢H2S的假设，这种天生的能力是它们在严重缺氧事件中生存的基础。本研究解决了13纹地松鼠（Ictidomys tridecemlineatus）大脑中的三个特定目标。第一个目的是确定地松鼠对吸入H2S的季节性反应，与大鼠相比。第二个目的是追踪缺氧暴露时分离线粒体和神经元中H2S的产生和代谢。第三个也是最后一个目的是评估啮齿类动物谱系中H2S产生和代谢关键基因的选择压力。预期所提出的研究将推进我们对允许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.