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Mitochondrial-Directed Therapy in Carbon Monoxide Poisoning

一氧化碳中毒的线粒体定向治疗

基本信息

批准号：
10057303
负责人：
DAVID H JANG
金额：
$ 25.71万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-16 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10057303
关键词：
Address Adverse effects Affect Animal Model Attenuated Bioenergetics Biological Markers Blood Cells Blood Platelets Brain Carbon Monoxide Carbon Monoxide Poisoning Carboxyhemoglobin Cardiac Cardiovascular system Cell Respiration Cell physiology Cells Cessation of life Complementary therapies Complication Confocal Microscopy Consequentialism Control Groups Critical Care Critical Illness Data Defect Diagnostic Disease Dose Effectiveness Emergency department visit Energy Metabolism Engineering Exhibits Exposure to Fire - disasters Gases Goals Heart Heart Injuries Hemoglobin Hospital Costs Hyperbaric Oxygen Hyperbaric Oxygenation Hyperbaric Therapy Hypoxia Immune Impairment In Vitro Injury Intervention Knowledge Lipid Peroxidation Maps Measures Mediating Medical Medical Societies Medicine Mitochondria Morbidity - disease rate Nervous System Trauma Neurologic Organ Pathway interactions Patients Peripheral Blood Mononuclear Cell Permeability Pharmacological Treatment Pharmacology Poisoning Prodrugs Proxy Publications Rattus Reactive Oxygen Species Research Research Personnel Respiration Rodent Control Secondary to Severity of illness Source Specificity Succinates Suicide attempt Supportive care System Therapeutic Time Tissues Toxic effect Toxicology Western Blotting Work base biomarker development clinical biomarkers clinically relevant complex IV disability drug development early detection biomarkers experience improved in vivo in vivo evaluation lost earning mitochondrial dysfunction mortality mouse model novel novel therapeutics organ injury point of care potential biomarker response standard care treatment strategy virtual

项目摘要

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.

一氧化碳（CO）是一种无色无味的气体，是每年引起中毒的重要原因。据估计，美国有 50,000 次急诊就诊，这是中毒的主要原因全球死亡。各种来源包括有故障的热发生器、自杀企图和火灾。估计美国一氧化碳中毒每年造成超过 10 亿美元的医院费用和收入损失。一氧化碳中毒具有很高的死亡率和发病率，对心血管和神经系统有影响。最随之而来的 CO 暴露的严重并发症是迟发性神经系统后遗症，发生率高达 50% 的患者。一氧化碳中毒有多种机制，如脂质过氧化和缺氧。我们自己的研究表明，CO 中线粒体功能（生物能和动态）发生了变化中毒。海底和高压医疗推荐的一氧化碳中毒标准治疗方法学会的是高压氧（HBO）疗法。此时，诊断和治疗都旨在早期支持治疗并选择使用高压疗法。然而，仍存在重大差距，包括：（1）缺乏用于衡量疾病严重程度的生物标志物； (2) 细胞水平上的机制理解有限线粒体功能（生物能量学和动力学）； (3)HBO治疗CO中毒疗效广泛针对 CO 造成的潜在线粒体功能障碍的治疗方法存在争议存在的并且； (4)缺乏任何护理点治疗。我们试图研究线粒体功能异常由外周血单核细胞 (PBMC) 和血小板 (PLT) 组成的血细胞针对组织一氧化碳中毒动物模型，并利用新的药理学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： • 一氧化碳中毒动物模型中线粒体功能的组织特异性变化是什么？ PBMC 和 PLT 可以作为大脑和心脏组织线粒体功能的代表吗？ • PBMC 和 PLT 能否作为早期线粒体功能障碍的可靠且信息丰富的标记物？一氧化碳中毒可以在疾病的亚临床阶段进行干预吗？ • 如何利用我们获得的数据来研究一氧化碳中毒的线粒体定向疗法解决目前缺乏针对一氧化碳中毒的护理点治疗的问题吗？我们的中心假设是线粒体功能因一氧化碳中毒而减弱我们基于机制的治疗将恢复正常的细胞功能。我们的长期目标拟议的研究旨在定义一氧化碳中毒中的特定线粒体缺陷并评估一种新疗法现在可用于体内使用。我们的团队目前拥有该药物的体外和体内使用经验与相关出版物复合。