权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

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.