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.

冬眠是哺乳动物的一种极端生理状况。小型冬眠动物，例如地松鼠，通过陷入深度麻木来度过冬天，在这种麻木状态下，重要的生理速率和新陈代谢急剧下降，体温显着下降。在整个冬眠过程中，动物会被周期性的觉醒打断，动物会在冬眠期间重新恢复正常的夏季体温，并恢复身体功能。作为这种剧烈循环的一部分，冬眠者自然会经历血流量减少和组织供氧耗尽（缺氧）。这种血液供应中断以及由此导致的缺氧对于包括人类在内的非冬眠者来说可能是致命的。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生产策略的理解，并可能突出与大脑低氧条件相关的治疗的新途径，例如作为中风。具体来说，研究人员检查了一条假设可以感知低氧条件并启动抑制细胞能量产生的反应的信号通路。为了评估该信号通路在自然冬眠者中的功能，研究人员检查了 13 系地松鼠的代谢和缺氧耐受性，并比较了哺乳动物之间的关键基因序列。该项目还进一步推进了国家科学基金会培训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员，以及通过社区健康改善中心和公共动物园进行公众宣传。小体型冬眠动物的众多生理谜团之一是它们对严重缺氧的显着耐受性，这种缺氧发生在从深度麻木发作中复温的过程中。该项目的目标是确定支持冬眠地松鼠在通常对缺氧敏感的组织（例如大脑）中的缺氧耐受性的机制。在小鼠等不耐缺氧的物种中，大脑中气体递质硫化氢 (H2S) 的急剧增加会抑制电子传递链，从而介导破坏性或致命性缺氧。该项目使用体内、体外和计算机方法来检验这样的假设：深度冬眠者的脑细胞能够代谢 H2S，并且这种先天能力是它们在严重缺氧事件中生存的基础。这项研究针对 13 系地松鼠 (Ictidomys tridecemlineatus) 大脑中的三个特定目标。第一个目标是确定地松鼠与老鼠相比对吸入硫化氢的季节性反应。第二个目标是追踪孤立线粒体和神经元缺氧期间 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内 H2S 产生和代谢关键基因的选择压力。预计拟议的研究将增进我们对冬眠者能够耐受脑缺氧的生化和生理适应的了解。