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性可以产生新的治疗靶点和干预措施，以治疗和预防许多人类疾病。例如，低血流量和氧气供应受限导致的心血管疾病，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。在冬眠的动物中，所有器官系统的血流量都在全局可逆地减少，但缺血/再灌注损伤不存在，因为血管供应的减少与新陈代谢的全局减少相匹配。最近的实验表明，通常不冬眠的哺乳动物可以通过暴露于含有低水平硫化氢（H2S）的空气中而进入完全可逆的冬眠状态，这种现象被称为H2S诱导的假死。人类冬眠样状态的快速诱导和受控逆转将立即适用于重症监护、创伤管理、器官移植和普通外科手术。此外，已知H2S可以抑制线粒体呼吸，最近被认为是一种内源性细胞信号分子，能够降低高血压和心血管疾病的进展，这表明H2S也可以用于治疗。然而，H2S的生理系统和细胞浓度以及导致H2S诱导的假死的浓度目前尚不清楚，并且对H2S诱导的假死期间改变的生理反应或靶向系统和线粒体反应知之甚少。利用我们实验室开发的新型极谱硫化氢传感器（PHSS），我们可以在生理条件下实时测量H2S，使我们能够为理解H2S诱导的假死状态做出独特的贡献。在一项合作研究中，我们建议定义H2S诱导的假死状态和恢复，表征血液H2S化学，并研究线粒体对H2S的反应。这将使我们能够验证H2S诱导非冬眠啮齿动物假死的机制假设，即当吸入H2S导致全血中溶解H2S浓度增加，导致组织中线粒体呼吸的可逆和保护性抑制时，会发生H2S诱导的假死。了解h2s诱导的假死机制将使我们能够测试药物干预在非冬眠哺乳动物中模拟冬眠条件的能力。对h2s诱导的假死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急性甚至长期心血管疾病患者的发病率和死亡率。公共卫生相关性：可以使用动物冬眠模型研究由低血流量和限氧引起的心血管疾病，如缺血/再灌注损伤和中风。最近的实验表明，通常不冬眠的哺乳动物可以通过暴露于含有低水平硫化氢（H2S）的空气中而进入完全可逆的冬眠状态，这种现象被称为H2S诱导的假死。对H2S诱导的假死模型进行更详细的定义，包括生理反应、血液H2S化学和线粒体机制，如本提案所述，将使该模型能够转化为人类，因为我们发现了可能改善许多急性甚至长期心血管疾病患者发病率和死亡率的新靶点。

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.