Mitochondrial Mechanisms of Hydrogen Sulfide Induced Suspended Animation

硫化氢诱导悬浮动画的线粒体机制

基本信息

批准号：
8105110
负责人：
SHANNON MARIE BAILEY
金额：
$ 36.25万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8105110
关键词：
Active Sites Acute Air Animals Area Bicarbonates Blood Blood Pressure Blood flow Blood specimen Body Temperature Breathing Calcium Cardiovascular Diseases Cardiovascular Pathology Cardiovascular system Chemistry Cleaved cell Consumption Critical Care Cytochromes Data Disease Progression Drops Exposure to Garlic Glutathione Disulfide Health Heart Hepatocyte Hibernation Human Hydrogen Sulfide Hypertension Intervention Investigation Ischemia Kinetics Knowledge Laboratories Lead Learning Liver Liver Mitochondria Lung Mammals Measurement Measures Membrane Potentials Metabolic Metabolism Mitochondria Modeling Molecular Morbidity - disease rate Operative Surgical Procedures Organ Organ Transplantation Oxidation-Reduction Oxygen Patients Permeability Physiological Physiology Production Recovery Reperfusion Injury Reperfusion Therapy Respiration Rodent Rodent Model Signal Transduction Signaling Molecule Site Stroke Sulfhydryl Compounds Sulfides Swelling Technology Testing Therapeutic Intervention Therapeutic Uses Time Tissues Translating Trauma Vascular blood supply Whole Blood absorption animation body system disulfide bond falls human disease improved mortality new therapeutic target novel oxidation polysulfide prevent research study response sensor tool uptake

项目摘要

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.

描述（由申请人提供）：对自然分子和细胞对极端环境条件的适应的研究可能会产生新的治疗靶点和干预措施，以治疗和预防多种人类疾病。例如，可以使用动物冬眠模型来研究由低血流量和有限的氧气供应引起的心血管病理，例如缺血/再灌注损伤和中风。在冬眠动物中，流向所有器官系统的血流量全面且可逆地减少，但不存在缺血/再灌注损伤，因为血管供应的减少与新陈代谢的整体减少相匹配。最近的实验表明，通常不冬眠的哺乳动物可以通过暴露在含有低水平硫化氢 (H2S) 的空气中而被诱导进入完全可逆的类冬眠状态，这种现象称为 H2S 引起的假死。人类冬眠状态的快速诱导和受控逆转将立即适用于重症监护、创伤处理、器官移植和一般外科手术。此外，已知能抑制线粒体呼吸的 H2S 最近被认为是一种内源性产生的细胞信号分子，能够减少高血压和心血管疾病的进展，这表明 H2S 也具有治疗用途。然而，H2S 的生理系统和细胞浓度以及导致 H2S 诱导假死的浓度目前尚不清楚，并且对于 H2S 诱导假死期间生理反应的改变或目标全身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进行实时 H2S 测量，使我们能够为理解 H2S 引起的假死状态做出独特的贡献。在合作中，我们建议定义 H2S 诱导的假死状态和恢复，表征血液 H2S 化学成分，并研究线粒体对 H2S 的反应。这将使我们能够检验以下机制假设：当吸入 H2S 导致全血中溶解的 H2S 浓度增加，从而导致组织中线粒体呼吸受到可逆和受保护的抑制时，非冬眠啮齿动物就会出现 H2S 引起的假死。了解 H2S 引起的假死机制将使我们能够测试药物干预模拟非冬眠哺乳动物物种冬眠状态的能力。对 H2S 引起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众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。公共健康相关性：可以使用动物冬眠模型来研究由低血流量和有限的氧气供应引起的心血管病理，例如缺血/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在含有低水平硫化氢 (H2S) 的空气中而被诱导进入完全可逆的类冬眠状态，这种现象称为 H2S 引起的假死。如本提案中所述，H2S 诱导的假死模型的更详细定义，包括生理反应、血液 H2S 化学和线粒体机制，将使该模型能够转化为人类，因为我们发现了可能改善发病率和许多患有急性甚至长期心血管疾病的患者死亡。