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：
10264056
负责人：
DAVID H JANG
金额：
$ 20.78万
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 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10264056
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）是一种无色且无味的气体，是每年中毒的重要原因估计在美国发生了50,000次急诊室访问，这是中毒的主要原因全球死亡。各种来源包括发电机故障，自杀企图和火灾。据估计美国的CO中毒每年导致超过10亿美元与医院费用和损失的收入有关。公司中毒具有高死亡率和发病率，在心血管和神经系统系统上的影响。最多结果CO暴露的严重并发症是延迟的神经系统续集，最多发生在50％中患者。有多种CO中毒的机制，例如脂质过氧化和缺氧。我们自己的工作表明，CO中的线粒体功能（既有生物能和动态）发生了变化。中毒。海底和高压医疗推荐的CO中毒的标准治疗方法社会是高压氧（HBO）治疗。目前，诊断和治疗均针对早期支持性护理并选择高压疗法。但是，存在重大差距，其中包括：（1）缺乏生物标志物以衡量疾病的严重程度；（2）关于细胞水平的机械理解有限线粒体功能（生物能和动力学）；（3）HBO对CO中毒的有效性广泛通过针对CO造成的潜在线粒体功能障碍的治疗辩论现有; （4）缺乏任何护理疗法。我们寻求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中的组织 CO中毒的动物模型，并利用新的药物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中毒的动物模型中，线粒体功能的组织特异性变化是什么 PBMC和PLT可以用作大脑和心脏组织线粒体功能的代理吗？ •PBMC和PLT可以用作早期线粒体功能障碍的可靠且内容丰富的标志可以在疾病的亚临床阶段进行干预的CO中毒？ •如何利用我们获得的数据来研究线粒体导向的CO中毒的疗法解决了缺乏对CO中毒的现有护理疗法的问题？我们的中心假设是，响应CO中毒而导致线粒体功能有所下降并且我们的基于机械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是在CO中毒中定义特定的线粒体缺陷并评估一种新的疗法现在可用于体内使用。我们的小组目前在体外和体内都有经验具有相关出版物的化合物。