The Use of Blood Cells and Optical Cerebral Complex IV Redox States in a Porcine Model of CO Poisoning with Evaluation of Mitochondrial Therapy

血细胞和光脑复合物 IV 氧化还原态在猪 CO 中毒模型中的应用及线粒体治疗的评价

• 批准号: 10734741
• 负责人: DAVID H JANG
• 金额: $ 70.98万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734741
• 关键词: Acute; Address; Affect; Alternative Therapies; Animal Model; Animals; Applications Grants; Award; Behavior assessment; Behavioral; Biological Markers; Blinded; Blood Cells; Carbon Monoxide; Carbon Monoxide Poisoning; Carboxyhemoglobin; Cardiac; Cause of Death; Cell physiology; Cells; Cerebrovascular Circulation; Cerebrum; Chronic; Cities; Clinical Trials; Complex; Data; Devices; Diagnostic; Disease Marker; Dose; Engineering; Evaluation; Exhibits; Exposure to; Extramural Activities; Family suidae; Fire - disasters; Functional disorder; Funding; Goals; Health; Heart Injuries; Hemoglobin; Home; Hour; Hyperbaric Oxygen; Hyperbaric Oxygenation; Hypoxia; Image; In Vitro; Inflammation; Institution; Intervention; Intervention Trial; Liquid substance; Magnetic Resonance Imaging; Measures; Methods; Mitochondria; Modeling; Monitor; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Nervous System Trauma; Neurocognitive; Neurocognitive Deficit; Neurologic; Optics; Outcome; Oxidation-Reduction; Oxygen; Oxygen Therapy Care; Pathway interactions; Patients; Permeability; Persons; Pharmacologic Substance; Physiological; Poisoning; Predictive Value; Prodrugs; Production; Prognosis; Publications; Randomized; Respiration; Role; Severities; Severity of illness; Succinates; Survivors; Sus scrofa; System; Technology; Testing; Therapeutic; Time; Translations; United States; Work; biomarker development; clinical application; clinical biomarkers; clinically relevant; complex IV; cytochrome c oxidase; disability; efficacy outcomes; exhaust; heart metabolism; in vivo; innovation; mitochondrial dysfunction; mortality; novel; novel strategies; novel therapeutic intervention; porcine model; pre-clinical; preservation; response; therapeutic development; tissue respiration; treatment effect; treatment response; treatment strategy

Our overarching goal is to advance understanding of mitochondrial mechanisms of carbon monoxide (CO) poisoning to develop diagnostics, therapeutics, and clinical trials. CO poisoning remains a major cause of death and disability, affecting 50,000 people per year in the United States alone. Patients removed from fires or following exposure to car and home generator exhaust are placed on 100% oxygen and transferred to a facility with a hyperbaric oxygen (HBO) delivery system. Despite the availability of HBO therapy centers in most major cities, inherent delays in access to and initiation of therapy greatly limit efficacy. In fact, even with HBO oxygen therapy a substantial number of surviving patients exhibit permanent neurocognitive impairments. This highlights an urgent need for alternative therapy. In the present proposal, we propose to study novel antidotal therapies for CO poisoning, based on our in vivo preliminary data that the use of a succinate prodrug relieves partial CIV inhibition caused by CO poisoning. Another existing gap is the lack of effective biomarkers to gauge severity, prognosis, and response to treatment. While a carboxyhemoglobin level is readily available at most institutions, its use is limited only to confirm exposure with no predictive value. The three main objectives our proposal seeks to address are: (1) extent of mitochondrial involvement for diagnostics and therapies; (2) limitations of current biomarkers to gauge severity of disease and treatment response; (3) lack of treatment strategies that target mitochondrial dysfunction to mitigate long-term neurologic and cardiac disability. Specifically for this A1 submission, we recently developed a novel survival swine model for CO poisoning with clinically relevant outcome metrics that include behavioral, imaging, and biomolecular measures. We also have obtained additional noninvasive optical data that also correlate with tissue respiration data. Another important feature of this proposal is the evaluation of a new treatment strategy involving a mitochondrial prodrug with the potential to shift existing treatment paradigm. We will also leverage our biomedical optics technology measuring cerebral blood flow, oxygenation, COHb and redox states of CIV in real time which will allow us to further elucidate the mechanisms of CO combined with repeat measures using two clinically relevant exposure duration with varying doses as well as prolonged low dose CO exposure. Aim 1 • To investigate the mitochondrial mechanisms that contribute to the neurologic and cardiac injury with the use of blood cell as a liquid biomarker in both acute AND early chronic CO poisoning. Aim 2 • Randomized, blinded pre-clinical intervention trial in swine models of CO poisoning to compare an engineered succinate prodrug to standard therapy of hyperbaric oxygen (HBO).

我们的首要目标是增进对碳线粒体机制的理解 一氧化碳 (CO) 中毒的诊断、治疗和临床试验。 仍然是死亡和残疾的主要原因，每年影响美国 50,000 人 单独从火中救出或接触汽车和家用发电机废气后的患者。 置于 100% 氧气中并转移至配有高压氧 (HBO) 输送系统的设施。 尽管大多数主要城市都设有 HBO 治疗中心，但就诊和治疗存在固有的延迟。 事实上，即使采用 HBO 氧疗，治疗的开始也极大地限制了疗效。 幸存的患者表现出永久性的神经认知障碍，这凸显了对这种药物的迫切需要。 在本提案中，我们建议研究新的 CO 解毒疗法。 中毒，根据我们的体内初步数据，使用琥珀酸前药可以缓解部分中毒 CO中毒引起的CIV抑制另一个现有的差距是缺乏有效的生物标志物。 碳氧血红蛋白水平很容易衡量严重程度、预后和治疗反应。 大多数机构都可以使用，但其用途仅限于确认暴露，没有预测价值。 我们的提案寻求解决的三个主要目标是：（1）线粒体参与的程度 诊断和治疗；（2）当前评估疾病严重程度的生物标志物的局限性； 治疗反应；（3）缺乏针对线粒体功能障碍的治疗策略来缓解 我们最近专门针对此 A1 提交开发了长期神经和心脏残疾。 一种新型的一氧化碳中毒存活猪模型，具有临床相关的结果指标，包括 我们还获得了其他非侵入性测量。 该提案的另一个重要特征也与组织呼吸数据相关。 是对涉及线粒体前药的新治疗策略的评估，该策略有可能 我们还将利用我们的生物医学光学技术测量来改变现有的治疗模式。 实时脑血流、氧合、COHb 和 CIV 氧化还原状态，这将使我们能够 使用两个临床相关的重复措施进一步阐明 CO 的机制 不同剂量的暴露持续时间以及长时间的低剂量 CO 暴露。 目标 1 • 研究有助于神经和心脏功能的线粒体机制 使用血细胞作为急性和早期慢性一氧化碳中毒的液体生物标志物造成的损伤。 目标 2 • 在 CO 中毒猪模型中进行随机、盲法临床前干预试验 将工程琥珀酸前药与高压氧 (HBO) 标准疗法进行比较。