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).

我们的首要目标是促进对碳的线粒体机制的理解。 一氧化碳(CO)中毒，以开发诊断、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5万人 独自一人。从火灾中转移或暴露在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。 尽管在大多数大城市都有HBO治疗中心，但进入和治疗中心的固有延误 开始治疗极大地限制了疗效。事实上，即使使用HBO氧疗，也有相当多的人 的幸存患者表现出永久性的神经认知障碍。这突显出迫切需要 另类疗法。在目前的提案中，我们建议研究CO的新解毒疗法 中毒，基于我们体内的初步数据，使用琥珀酸前药可以部分缓解 一氧化碳中毒引起的CIV抑制。另一个现有的差距是缺乏有效的生物标记物来 评估病情严重程度、预后和治疗反应。而碳氧血红蛋白水平很容易 在大多数机构都可以使用，但它的使用仅限于确认风险敞口，没有预测价值。这个 我们的提案试图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)当前生物标志物在衡量疾病严重程度和 治疗反应；(3)缺乏针对线粒体功能障碍的治疗策略来缓解 长期的神经性和心脏功能障碍。专门针对这份A1提交，我们最近开发了 一种新的一氧化碳中毒存活猪模型，其临床相关结果指标包括 行为、成像和生物分子测量。我们还获得了额外的非侵入性 光学数据也与组织呼吸数据相关。这项提议的另一个重要特点 是对一种新的治疗策略的评估，该策略涉及一种线粒体前药，具有潜在的 改变现有的治疗模式。我们还将利用我们的生物医学光学测量技术 CIV的脑血流、氧合、COHb和氧化还原状态的实时监测，这将使我们能够 用两个临床相关的方法进一步阐明CO合并重复措施的机制 不同剂量的暴露持续时间以及延长的低剂量CO暴露。 目的1·探讨线粒体在神经学和心脏疾病中的作用机制 在急性和早期慢性一氧化碳中毒中使用血细胞作为液体生物标记物的损伤。 目的2.猪一氧化碳中毒模型的随机、盲法临床前干预试验 将经过改造的琥珀酸前药与高压氧(HBO)的标准疗法进行比较。