Mitochondrial-Directed Therapy in Carbon Monoxide Poisoning

一氧化碳(CO)是一种无色无味的气体，是每年中毒的重要原因 据估计，美国有5万急诊科就诊，这是中毒的主要原因 全球范围内的死亡。各种来源包括有故障的热源、自杀企图和火灾。据估计， 在美国，一氧化碳中毒每年导致超过10亿美元的医疗费用和收入损失。公司 中毒的死亡率和发病率都很高，对心血管和神经系统都有影响。最多的 继发性一氧化碳暴露的严重并发症是迟发性神经后遗症，发生率高达50% 病人的数量。CO中毒的机制有多种，如脂质过氧化、缺氧等。我们自己的 研究表明，在一氧化碳中存在线粒体功能的改变(包括生物能量和动力) 下毒了。海底高压医学会推荐的一氧化碳中毒标准救治 社会是高压氧(HBO)疗法。此时，无论是诊断还是治疗都是针对早期 支持性护理和选择使用高压氧治疗。然而，存在着显著的差距，包括：(1)缺乏 衡量疾病严重程度的生物标记物；(2)在细胞水平上对以下方面的机械理解有限 对线粒体功能的影响(生物能量学和动力学)；(3)高压氧治疗一氧化碳中毒的效果广泛 与针对一氧化碳造成的潜在线粒体功能障碍的治疗展开辩论几乎不是 存在；(4)缺乏任何护理疗法。我们试图研究线粒体功能异常在 由外周血单核细胞(PBMC)和血小板(PLT)组成的血细胞抗组织 一氧化碳中毒动物模型及利用新的药理策略直接改善线粒体 功能。我们建议解决与线粒体功能相关的关键问题： ·在CO中毒动物模型中，线粒体功能的组织特异性变化是什么？ PBMCs和PLT能否作为大脑和心脏组织线粒体功能的代用品？ ·PBMCs和PLT是否可以作为早期线粒体功能障碍的可靠和信息标记物 哪些一氧化碳中毒可以在疾病的亚临床阶段进行干预？ ·我们获得的数据如何被用于研究一氧化碳中毒的线粒体定向治疗 解决现有的针对CO中毒的护理点疗法的不足？ 我们的中心假设是，一氧化碳中毒会导致线粒体功能下降 我们的机械性治疗将恢复正常的细胞功能。我们的长期目标是 建议的研究是确定一氧化碳中毒的特定线粒体缺陷并评估一种新的治疗方法 现在可以在体内使用。我们小组目前在体外和体内使用这种药物方面都有经验。 与相关出版物进行复合。

Carbon monoxide (CO) is a colorless and odorless gas that is an important cause of poisoning annually with an estimated 50,000 emergency department visits occurring in the US and it is a leading cause of poisoning death globally. Various sources include faulty heat generators, suicidal attempts and fires. It is estimated that CO poisoning in the US results in over $1 billion annually related to hospital costs and lost earnings. CO poisoning has high mortality and morbidity with effects at the cardiovascular and neurologic system. The most serious complication of consequential CO exposure is delayed neurological sequela which occurs in up to 50% of patients. There are multiple mechanisms of CO poisoning such as lipid peroxidation and hypoxia. Our own work demonstrates that there are alterations in mitochondrial function (both bioenergetic and dynamic) in CO poisoning. The standard treatment for CO poisoning recommended by the Undersea & Hyperbaric Medical Society is hyperbaric oxygen (HBO) therapy. At this time, both diagnostics and treatments are aimed at early supportive care and select use of hyperbaric therapy. However, there are significant gaps that include: (1) lack of biomarkers to gauge severity of disease; (2) limited mechanistic understanding at a cellular level with regard to mitochondrial function (bioenergetics and dynamics); (3) the effectiveness of HBO for CO poisoning is widely debated with treatment aimed at the underlying mitochondrial dysfunction imposed by CO being virtually non- existent and; (4) lack of any point of care therapy. We seek to investigate abnormal mitochondrial function in blood cells consisting of peripheral blood mononuclear cells (PBMCs) and platelets (PLTs) against tissue in an animal model of CO poisoning and to utilize a new pharmacological strategy to directly improve mitochondrial function. We propose to address the critical issues relevant to mitochondrial function: • What is the tissue-specific changes in mitochondrial function in an animal model of CO poisoning and can PBMCs and PLTs serve as a proxy for tissue mitochondrial function for the brain and heart? • Can PBMCs and PLTs serve as a reliable and informative marker of early mitochondrial dysfunction in CO poisoning which may enable intervention in the subclinical stages of disease? • How can our data obtained be leveraged to study mitochondrial-directed therapy in CO poisoning to address the lack of any existing point of care therapy for CO poisoning? Our central hypothesis is that there are decrements in mitochondrial function in response to CO poisoning and that our mechanistic-based treatment will restore normal cellular function. The long-term goals of our proposed research are to define specific mitochondrial defects in CO poisoning and evaluate a novel therapy now available for in vivo use. Our group currently has experience in both the in vitro and in vivo use of this compound with relevant publications.