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).

我们的总体目标是提高对碳线粒体机制的理解 一氧化物（CO）中毒以开发诊断，治疗和临床试验。共同中毒 仍然是死亡和残疾的主要原因，在美国每年影响50,000人 独自的。从火灾中撤离或暴露于汽车和家庭发电机排气后的患者是 放置在100％氧气上，并通过高压氧（HBO）递送系统转移到设施中。 尽管大多数主要城市都有HBO治疗中心的可用性，但继承了进入和 启动治疗大大限制了效率。实际上，即使使用HBO氧疗法 生存患者表现出永久性神经认知障碍。这突出了迫切需要 替代疗法。在本提案中，我们建议研究CO的新型解毒疗法 中毒，基于我们的体内初步数据，即琥珀酸盐前药的使用部分 COI中毒引起的CIV抑制。现有的另一个差距是缺乏有效的生物标志物 衡量严重程度，预后和对治疗的反应。羧基血红蛋白水平很容易 在大多数机构中可用，其使用仅限于确认没有预测价值的曝光。这 我们的提议寻求解决的三个主要目标是：（1）线粒体参与的程度 诊断和疗法； （2）当前生物标志物限制疾病严重程度和 治疗反应； （3）缺乏针对线粒体功能障碍的治疗策略来减轻 长期神经和心脏残疾。特别是对于此A1提交，我们最近开发了 一种新型的生存猪模型，用于与临床相关的结果指标中毒 行为，成像和生物分子测量。我们还获得了其他无创的 与组织呼吸数据相关的光学数据。该提议的另一个重要特征 是对涉及线粒体前药的新治疗策略的评估 改变现有的治疗范式。我们还将利用我们的生物医学光学技术测量 实时的脑血流，氧合，COHB和CIV的氧化还原状态，这将使我们得以实时 进一步阐明了CO的机制，并使用两个临床相关的重复测量 暴露持续时间有不同的剂量以及长时间的低剂量CO暴露。 目标1•研究有助于神经系统和心脏的线粒体机制 在急性和早期慢性CO中毒中使用血细胞作为液体生物标志物的损伤。 目标2•在CO中毒的猪模型中，随机，盲目的临床前干预试验 将工程化的琥珀酸药物与高压氧（HBO）的标准疗法进行比较。