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

• 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
• 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

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 据估计，美国有5万急诊科就诊，这是导致 在全球范围内毒死。各种来源包括有故障的热源、自杀企图和火灾。它是 据估计，在美国，一氧化碳中毒每年造成超过10亿美元的医院费用和损失 收入。一氧化碳中毒的死亡率和发病率很高，对心血管和神经系统都有影响。 系统。继发性一氧化碳暴露最严重的并发症是延迟性神经后遗症 发生在高达50%的幸存者身上。然而，心脏后遗症以及潜在的后遗症定义较少。 可能发生的细胞功能障碍。我们自己的研究表明，线粒体发生了变化 在CO中毒中的作用(包括生物能量学和动力学)。一氧化碳中毒的标准治疗 由海底和高压医学会推荐的高压氧(HBO)疗法。对此 时间上，诊断和治疗的目的都是为了早期支持性护理和选择使用高压氧治疗。 关于目前可用的生物标志物和一氧化碳中毒的治疗需要一种新的 一种机制驱动的治疗方法。根据这些现有的差距，正在进行调查 主要基于对小动物的研究来改进治疗。然而，许多监督机构 毒理学测试需要同时使用啮齿动物和非啮齿动物物种，而目前缺乏这一点。有一个 缺乏大型动物模型来研究一氧化碳中毒的细胞功能障碍和潜在的治疗方法。 R03提案试图解决的主要限制如下：(1)有限的机械性 在细胞水平上了解线粒体的功能(生物能量学和动力学)； 一氧化碳中毒对心血管的不利影响以及可能发生的潜在细胞功能障碍； 缺乏足够的大型动物模型来更接近地模拟人类生理。 我们建议用家猪(Sus Scrofa)建立一氧化碳中毒的大型动物模型 国内)。猪可以被认为是生物医学研究的翻译模型，因为解剖学， 在生理和生化方面与人类相似。本R03提案得到了初步的支持 确保成功的数据和可行性。少年派(张)目前持有NHLBI K08奖，并将 特别是利用他在线粒体领域的K支持的研究技能和技术 在他的系主任(Ben Sun，医学博士)和K08导师(Todd Kilbaugh，医学博士)的全力支持下 MD)以及包含最先进设备的卓越环境。数据和 获得该R03奖项的方法将允许PI提交具有竞争力的R01作为ESI。