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Development of a Porcine Model of Carbon Monoxide Poisoning to Evaluate Cardiac and Mitochondrial Dysfunction

开发一氧化碳中毒猪模型以评估心脏和线粒体功能障碍

基本信息

批准号：
10063393
负责人：
DAVID H JANG
金额：
$ 7.48万
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：
2020-08-03 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063393
关键词：
Acute Address Affect Air Anatomy Animal Model Animal Testing Alternatives Animals Area Award Biochemical Bioenergetics Biological Markers Biology Biomedical Research Canis familiaris Carbon Monoxide Carbon Monoxide Poisoning Cardiac Cardiovascular system Case Study Catheters Cause of Death Cessation of life Cities Clinical Complication Consequentialism Critical Illness Data Department chair Detection Development Diagnostic Disease Disease model Domestic Pig Dose Drosophila genus Electron Transport Emergency department visit Ensure Environment Equipment Exhibits Exposure to Family suidae Fire - disasters Functional disorder Funding Gases Genetic Goals Heart Abnormalities Heart Injuries Hospital Costs Human Human Biology Hyperbaric Oxygen Hyperbaric Oxygenation Hyperbaric Therapy Impairment Injury Investigation Isoflurane Knowledge Maps Measurement Measures Medical Societies Medicine Mentors Metabolic Biotransformation Metabolic Pathway Methods Mitochondria Modeling Molecular Morbidity - disease rate Myocardial dysfunction National Heart, Lung, and Blood Institute Nervous System Trauma Neurologic Non-Rodent Model Organism Pathway interactions Patients Phenotype Physiologic intraventricular pressure Physiological Physiology Poisoning Reactive Oxygen Species Reporting Research Research Personnel Research Support Resources Respiration Retrospective Studies Rodent Source Specificity Suicide attempt Supportive care Survivors Sus scrofa System Techniques Testing The Sun Therapy Clinical Trials Time Toxic effect Toxicology Training Translating Tube United States Work Xenobiotics Zebrafish base career clinical application clinically relevant disability dosage endotracheal experience heart function human disease improved in vivo innovation lost earning mitochondrial dysfunction mortality mouse model new therapeutic target nonhuman primate novel strategies novel therapeutics organ injury preclinical trial pressure protein expression response skills standard care success translational model

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 survivors. However, the cardiac sequalae is less defined as well as the underlying cellular dysfunction that may occur. 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. There is significant debate with currently available biomarkers and treatment for CO poisoning requiring a new approach to therapy that is mechanism-driven. Based on these existing gaps, there are ongoing investigations for improved treatment based primarily on small animal studies. However, many agencies that oversee toxicological testing require use of both rodent and non-rodent species which is lacking at this time. There is a paucity of large animal models to study both cellular dysfunction and potential therapy in CO poisoning. The primary limitations that this R03 proposal seeks to address are the following: (1) limited mechanistic understanding at a cellular level with regard to mitochondrial function (bioenergetics and dynamics); (2) the adverse cardiovascular effects of CO poisoning and the underlying cellular dysfunction that may occur; (3) the lack of adequate large animal models that more closely mimic human physiology. We propose to develop a large animal model of CO poisoning using the domestic pig (Sus scrofa domesticus). The pig may be considered a translational model of biomedical research because of anatomical, physiological and biochemical similarity to humans. This R03 proposal is strongly supported by preliminary data and feasibility that will ensure success. The PI (Jang) currently holds a NHLBI K08 award and will specifically leverage his K-supported research skills and techniques focused in the area of mitochondrial medicine with the full support of both his departmental chair (Ben Sun, MD) and K08 mentor (Todd Kilbaugh, MD) along with the outstanding environment that incorporates state-of-the-art equipment. The data and methods obtained with this R03 award will allow the PI to submit a competitive R01 as an ESI.

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