The Role of Hydrogen Sulfide in the Hypoxia Tolerance of Hibernators

硫化氢在冬眠者耐缺氧性中的作用

• 批准号: 1929592
• 负责人: Allyson Hindle
• 金额: $ 16.4万
• 依托单位: University of Nevada Las Vegas
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1929592&HistoricalAwards=false
• 关键词: Role; Hydrogen; Sulfide; Hypoxia; Tolerance

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.

冬眠是哺乳动物中极端的生理状况。小型冬眠（例如地松鼠）通过陷入冬季的深度曲折，在冬季中生存，其中重要的生理速率和代谢大大降低，体温大大下降。 Torpor在整个冬眠过程中都被周期性的唤醒打断，其中动物会重新变形至正常的夏季体温，并恢复身体的功能。作为这种戏剧性循环的一部分，冬眠自然会降低血液流量和耗尽组织的氧气供应（缺氧）。血液供应和导致的缺氧的这种干扰可能对包括人类在内的非爆炸者致命。通过检查冬眠的松鼠如何在关键组织（例如大脑）中的氧气水平较低，该项目扩大了我们对所有哺乳动物中细胞能量产生策略的理解，并可能突出显示与大脑低氧相关的疗法的新途径，例如中风。具体而言，研究人员检查了一种信号传导途径，该信号传导途径假设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天然冬眠中的功能，研究人员检查了13层的松鼠中的代谢和缺氧耐受性，并比较哺乳动物中关键基因的序列。该项目还将进一步培训新一代科学家的目标，并为公众提供科学发现：该项目包括对本科生和博士后研究人员的培训，以及通过社区健康改善中心和公共动物园的公共宣传。小型冬眠者的众多生理奥秘之一是它们对严重缺氧的明显耐受性，这是在深毛发爆发中引起的唤醒期间发生的。该项目的目的是确定支持正常缺氧敏感组织（如大脑）中冬眠地松鼠低氧耐受性的机制。在耐高氧耐受的物种（如小鼠）中，由于抑制电子传输链的耐热质氢（H2S）的急性增加，在大脑中介导了破坏或致死性缺氧。该项目在体内，体外和计算机方法中使用了以下假设：深冬眠器的脑细胞能够代谢H2s，并且这种先天能力是其严重低氧事件的生存的基础。这项研究解决了13层地松鼠（Ictidomys tridecemlineatus）大脑中的三个特定目标。与大鼠相比，第一个目标是确定地松鼠对吸入H2S的季节性反应。第二个目标是在孤立的线粒体和神经元中缺氧期间跟踪H2S的产生和代谢。第三个也是最后一个目标是评估啮齿动物谱系中H2S生产和代谢的关键基因的选择性压力。预计拟议的研究将促进我们对生化和生理适应的了解，从而使冬眠耐受性缺氧。