The Use of Blood Cells as a Biomarker in a Porcine Model of CO Poisoning with Evaluation of an Engineered Succinate-Prodrug

使用血细胞作为一氧化碳中毒猪模型中的生物标志物并评估工程琥珀酸前药

• 批准号: 10276252
• 负责人: DAVID H JANG
• 金额: $ 69.73万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10276252
• 关键词: Acute; Address; Affect; Alternative Therapies; Animal Model; Animals; Antidotes; Applications Grants; Biological Markers; Blinded; Blood Cells; Brain; Carbon Monoxide; Carbon Monoxide Poisoning; Carboxyhemoglobin; Cardiac; Cause of Death; Cell physiology; Cells; Cerebrovascular Circulation; Cerebrum; Cities; Clinical; Complex; Data; Diagnostic; Dose; Electron Transport; Engineering; Ensure; Evaluation; Exhibits; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Exposure to; Family suidae; Fire - disasters; Functional disorder; Goals; Health; Heart; Heart Injuries; Hemoglobin; Home; Hour; Human; Hyperbaric Oxygen; Hyperbaric Oxygenation; Inflammation; Injury; Institution; Intervention; Intervention Trial; Liquid substance; Measures; Metabolic; Methods; Mitochondria; Modeling; Monitor; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Nervous System Trauma; Neurocognitive; Neurocognitive Deficit; Neurologic; Organ; Outcome; Oxygen; Oxygen Therapy Care; Pathway interactions; Patients; Permeability; Pharmacologic Substance; Physiological; Physiology; Poisoning; Predictive Value; Prodrugs; Production; Prognosis; Publications; Randomized; Reactive Oxygen Species; Reproducibility; Research Personnel; Respiration; Role; Severities; Severity of illness; Specimen; Succinates; Survivors; Sus scrofa; System; Testing; Therapeutic; Therapeutic Clinical Trial; Tissues; Toxic effect; United States; Work; base; career; clinical application; clinical biomarkers; complex IV; cytochrome c oxidase; disability; efficacy outcomes; exhaust; heart function; heart metabolism; mitochondrial dysfunction; mortality; novel; porcine model; pre-clinical; preservation; protein expression; response; success; 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 ex vivo findings 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) limited mechanistic understanding of the key role the mitochondria has in CO poisoning; (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. This project will define the mitochondrial pathways involved in CO poisoning using blood cells compared against brain and cardiac tissue in a porcine model of CO poisoning, furthering the mechanistic understanding of CO poisoning. 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. To achieve these objectives, a large animal trial in a porcine model of CO poisoning is proposed with the following aims: Aim 1 • To establish the mitochondrial mechanisms that contribute to the neurologic and cardiac injury that occur in CO poisoning and assess blood cell mitochondrial function as a potential liquid biomarker. Aim 2 • Randomized, blinded pre-clinical intervention trial in porcine 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。一氧化碳中毒 仍然是死亡和残疾的主要原因，每年影响美国 50,000 人 独自的。从火场中救出或接触汽车和家用发电机废气后的患者 置于 100% 氧气中并转移至配备高压氧 (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。 治疗的开始极大地限制了疗效。事实上，即使采用 HBO 氧疗，仍有相当多的人 的幸存患者表现出永久性的神经认知障碍。这凸显了迫切需要 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，根据我们的离体发现，使用琥珀酸前药可以缓解部分 CIV 抑制CO中毒引起的。另一个现有的差距是缺乏有效的生物标志物来衡量 严重程度、预后和治疗反应。虽然碳氧血红蛋白水平很容易获得 在大多数机构，其用途仅限于确认暴露，没有预测价值。三个 我们的提案寻求解决的主要目标是：（1）对关键的机械理解有限 线粒体在 CO 中毒中的作用； (2) 目前生物标志物在衡量疾病严重程度方面的局限性 疾病和治疗反应； (3)缺乏针对线粒体功能障碍的治疗策略 减轻长期神经和心脏残疾。该项目将定义线粒体 使用血细胞与大脑和心脏组织进行比较，研究涉及一氧化碳中毒的途径 一氧化碳中毒猪模型，进一步加深了对一氧化碳中毒机制的认识。其他 该提案的一个重要特点是评估一种新的治疗策略，涉及 线粒体前药有可能改变现有的治疗模式。为了实现这些 为了实现这一目标，建议在猪 CO 中毒模型中进行一项大型动物试验，结果如下： 目标： 目标 1 • 建立有助于神经系统和功能的线粒体机制。 CO 中毒中发生的心脏损伤并评估血细胞线粒体功能 潜在的液体生物标志物。 目标 2 • 在猪 CO 中毒模型中进行随机、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。