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).

我们的首要目标是促进对碳的线粒体机制的理解 一氧化碳（CO）中毒的诊断，治疗和临床试验。CO中毒 仍然是导致死亡和残疾的主要原因，每年影响美国5万人 一个人从火灾中或暴露于汽车和家用发电机废气中的患者， 置于100%氧气中并转移到具有高压氧（HBO）输送系统的设施中。 尽管大多数大城市都有HBO治疗中心，但在获得和治疗方面存在固有的延迟， 治疗开始大大限制了疗效。事实上，即使有HBO氧气治疗， 的存活患者表现出永久性神经认知障碍。这突出表明迫切需要 替代疗法在本提案中，我们建议研究新的CO解毒疗法， 中毒，基于我们的离体发现，使用琥珀酸酯前药缓解部分CIV 一氧化碳中毒引起的抑制。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、预后和对治疗的反应。虽然碳氧血红蛋白水平很容易获得 在大多数机构，其使用仅限于确认接触，没有预测价值。三 我们的建议旨在解决的主要目标是：（1）对关键的有限的机械理解 线粒体在一氧化碳中毒中的作用;（2）目前生物标志物在衡量一氧化碳中毒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 以减轻长期的神经和心脏残疾。这个项目将定义线粒体 使用血细胞与脑和心脏组织比较， 猪CO中毒模型，进一步了解CO中毒的机制。另一 这项建议的一个重要特点是评估一种新的治疗策略， 线粒体前药，具有改变现有治疗模式的潜力。实现这些 目的，在猪模型中进行一氧化碳中毒的大型动物试验， 目的： 目的1 ·建立线粒体机制，促进神经和 一氧化碳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。 目的2 ·在猪CO中毒模型中进行随机、盲法临床前干预试验 比较工程化琥珀酸酯前药与高压氧（HBO）的标准治疗。