Mitochondrial Mechanisms of Hydrogen Sulfide Induced Suspended Animation

描述(由申请人提供)：研究自然分子和细胞对极端环境条件的适应可能会产生新的治疗目标和干预措施，以治疗和预防许多人类疾病。例如，低血流量和有限氧气供应引起的心血管病理，如缺血/再灌注损伤和中风，可以使用动物冬眠模型进行研究。在冬眠动物中，流向所有器官系统的血液流动是全局的和可逆的，但不存在缺血/再灌注损伤，因为血管供应的减少与全球新陈代谢的减少相匹配。最近的实验表明，正常情况下不冬眠的哺乳动物可以通过暴露在含有低水平硫化氢(H2S)的空气中来诱导进入完全可逆的类冬眠状态，这种现象被称为硫化氢诱导的暂停生命。快速诱导和可控地逆转人类的冬眠状态将立即适用于重症监护、创伤处理、器官移植和普通外科手术。此外，众所周知可以抑制线粒体呼吸的硫化氢，最近被认为是一种内源性产生的细胞信号分子，能够减缓高血压和心血管疾病的进展，这表明硫化氢也有治疗用途。然而，硫化氢的生理、系统和细胞浓度以及导致硫化氢诱导的暂停死亡的浓度目前尚不清楚，对硫化氢诱导的暂停死亡过程中改变的生理反应或靶向的全身和线粒体反应也知之甚少。利用本实验室研制的新型极谱硫化氢传感器(PHSS)，对生理条件下的硫化氢进行了实时测量，为理解硫化氢诱导的悬浮状态做出了独特的贡献。在一项合作工作中，我们建议定义硫化氢诱导的暂停生命状态和恢复，表征血液中的硫化氢化学，并研究线粒体对硫化氢的反应。这将使我们能够测试机制假说，即当吸入硫化氢导致全血中溶解的硫化氢浓度增加，从而导致组织中线粒体呼吸的可逆和保护性抑制时，非冬眠啮齿动物中会发生硫化氢诱导的暂缓死亡。了解硫化氢诱导的暂停死亡的机制将使我们能够测试药物干预的能力，以模拟非冬眠哺乳动物物种的冬眠状态。对硫化氢诱导的暂停生命模型进行更详细的研究和定义将发现新的靶点，这些靶点可能会改善许多患有急性甚至长期心血管疾病的患者的发病率和死亡率。PUBLIIC健康相关性：可以使用动物冬眠模型来研究低血流量和有限氧气供应引起的心血管病理，如缺血/再灌注损伤和中风。最近的实验表明，正常情况下不冬眠的哺乳动物可以通过暴露在含有低水平硫化氢(H2S)的空气中来诱导进入完全可逆的类冬眠状态，这种现象被称为硫化氢诱导的暂停生命。对硫化氢诱导的暂停生命模型的更详细的定义，包括生理反应、血液中的硫化氢化学和线粒体机制，将使这一模型能够被翻译到人类身上，因为我们发现了新的靶点，可能会改善许多患有急性或长期心血管疾病的患者的发病率和死亡率。

DESCRIPTION (provided by applicant): The study of natural molecular and cellular adaptations to extreme environmental conditions could result in new therapeutic targets and interventions to treat and prevent numerous human diseases. For example, cardiovascular pathologies resulting from low blood flow and limited O2 supply, such as ischemia/reperfusion damage and stroke, can be studied using animal hibernation models. In hibernating animals, blood flow is globally and reversibly reduced to all organ systems, but ischemia/ reperfusion insults are absent as the reduced vascular supply is matched by global reduction in metabolism. Recent experiments have demonstrated that mammals that do not normally hibernate can be induced to enter a fully reversible hibernation-like state by exposure to air containing low levels of hydrogen sulfide (H2S) in a phenomenon called H2S-induced suspended animation. Rapid induction and controlled reversal of a hibernation-like state in humans would be immediately applicable for critical care, trauma management, organ transplantation, and general surgical procedures. Moreover, H2S, which is known to inhibit mitochondrial respiration, has recently gained recognition as an endogenously produced cell signaling molecule capable of reducing hypertension and cardiovascular disease progression, suggesting therapeutic uses for H2S as well. However, physiological systemic and cellular concentrations of H2S and those that lead to H2S-induced suspended animation are currently unknown, and very little is understood about the altered physiological responses or targeted systemic and mitochondrial responses during H2S-induced suspended animation. With a novel polarographic hydrogen sulfide sensor (PHSS) developed in our laboratory, we make real time H2S measurements under physiological conditions, allowing us to make unique contributions to the understanding of the H2S-induced suspended animation state. In a collaborative effort, we propose to define the H2S-induced suspended animation state and recovery, to characterize blood H2S chemistry, and to investigate mitochondrial responses to H2S. This will allow us to test the mechanistic hypothesis that H2S-induced suspended animation in non-hibernating rodents occurs when inhaled H2S causes an increased concentration of dissolved H2S in whole blood that results in reversible and protected suppression of mitochondrial respiration in tissues. Learning the mechanisms of H2S-induced suspended animation will allow us to test the ability of pharmacologic interventions to mimic conditions of the hibernator in non-hibernating mammalian species. A more detailed investigation and definition of the H2S-induced suspended animation model will uncover novel targets that may improve the morbidity and mortality of numerous patients with acute or even long term cardiovascular pathologies. PUBLIIC HEALTH RELEVANCE: Cardiovascular pathologies resulting from low blood flow and limited oxygen supply, such as ischemia/reperfusion damage and stroke, can be studied using animal hibernation models. Recent experiments have demonstrated that mammals that do not normally hibernate can be induced to enter a fully reversible hibernation-like state by exposure to air containing low levels of hydrogen sulfide (H2S) in a phenomenon called H2S-induced suspended animation. A more detailed definition of the H2S-induced suspended animation model, including physiological responses, blood H2S chemistry and mitochondrial mechanisms, as described in this proposal, will enable this model to be translated to humans as we uncover novel targets that may improve the morbidity and mortality of numerous patients with acute or even long term cardiovascular pathologies.