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

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，开发诊断，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，基于我们的体内初步数据，使用琥珀酸酯前药缓解了部分 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， 评估严重程度、预后和治疗反应。虽然碳氧血红蛋白水平很容易 虽然大多数机构都有这种方法，但其用途仅限于确认接触情况，没有预测价值。的 我们的建议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）目前生物标志物在衡量疾病严重程度方面的局限性， 治疗反应;（3）缺乏针对线粒体功能障碍的治疗策略，以减轻 长期的神经和心脏残疾特别是针对A1提交，我们最近开发了 一氧化碳中毒的新型存活猪模型，具有临床相关结局指标，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 也与组织呼吸数据相关的光学数据。这项提案的另一个重要特点是 是评估一种新的治疗策略，涉及一种线粒体前药， 改变现有的治疗模式。我们还将利用我们的生物医学光学技术测量 脑血流量、氧合、COHb和CIV的氧化还原状态的真实的时间，这将使我们能够 使用两种临床相关的重复测量进一步阐明CO的机制， 不同剂量的暴露持续时间以及长时间低剂量CO暴露。 目的1 ·研究线粒体参与神经和心脏功能的机制， 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。 目的2 ·在猪CO中毒模型中进行随机、设盲临床前干预试验， 将工程化琥珀酸酯前药与高压氧（HBO）的标准治疗进行比较。

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).