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：
10228097
负责人：
DAVID H JANG
金额：
$ 7.5万
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10228097
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 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 cardiovascular effects 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 porcine model 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）是一种无色且无味的气体，是每年中毒的重要原因美国估计有50,000次急诊室就诊，这是全球中毒死亡。各种来源包括发电机故障，自杀企图和火灾。这是据估计，美国的CO中毒每年导致超过10亿美元与医院费用相关并损失收益。 CO中毒具有高死亡率和发病率，在心血管和神经系统上的影响系统。结果CO暴露的最严重并发症是延迟的神经段，在多达50％的幸存者中发生。但是，心脏序列的定义较低，而基础则是可能发生的细胞功能障碍。我们自己的作品表明线粒体发生了变化 CO中毒中的功能（既有生物能和动态）。 CO中毒的标准治疗海底和高压医学协会推荐的是高压氧（HBO）疗法。在这个时间，诊断和治疗均针对早期的支持性护理，并选择使用高压疗法。当前可用的生物标志物和用于CO中毒的治疗需要新的辩论治疗方法是机理驱动的。基于这些现有差距，正在进行中的调查主要基于小动物研究改进治疗。但是，许多监督的机构毒理学测试需要目前缺乏啮齿动物和非岩体物种。有一个大型动物模型的稀少性研究了CO中毒中的细胞功能障碍和潜在治疗。该R03提案寻求解决的主要限制是：（1）机械限制了解线粒体功能（生物能和动力学）在细胞水平上的理解；（2） CO中毒的不良心血管影响和可能发生的基本细胞功能障碍；（3）缺乏足够的大型动物模型，更像人类生理。我们建议使用家用猪开发大型的CO中毒动物模型（Sus Scrofa forextus）。由于解剖学，与人类的生理和生化相似性。此R03提案得到了初步的强烈支持数据和可行性将确保成功。 PI（Jang）目前持有NHLBI K08奖，将特别利用他的K支持的研究技巧和技术集中在线粒体领域医学在他的部门主席（Ben Sun，MD）和K08 Mentor（Todd Kilbaugh，todd Kilbaugh， MD）以及包括最先进设备的杰出环境。数据和通过此R03奖获得的方法将使PI可以提交具有竞争力的R01作为ESI。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Preliminary Research: Application of Non-Invasive Measure of Cytochrome c Oxidase Redox States and Mitochondrial Function in a Porcine Model of Carbon Monoxide Poisoning.

初步研究：细胞色素c氧化酶氧化还原状态和线粒体功能的非侵入性测量在一氧化碳中毒猪模型中的应用。

DOI：
10.1007/s13181-022-00892-5
发表时间：
2022
期刊：
Journal of medical toxicology : official journal of the American College of Medical Toxicology
影响因子：
0
作者：
Lewis,Alistair;Forti,RodrigoM;Alomaja,Oladunni;Mesaros,Clementina;Piel,Sarah;Greenwood,JohnC;Talebi,FatimaM;Mavroudis,ConstantineD;Kelly,Matthew;Kao,Shih-Han;Shofer,FrancesS;Ehinger,JohannesK;Kilbaugh,ToddJ;Baker,WesleyB
通讯作者：
Baker,WesleyB

Succinate prodrugs as treatment for acute metabolic crisis during fluoroacetate intoxication in the rat.

DOI：
10.1007/s11010-022-04589-9
发表时间：
2023-06
期刊：
Molecular and cellular biochemistry
影响因子：
4.3
作者：
通讯作者：

Imaging of White Matter Injury Correlates with Plasma and Tissue Biomarkers in Pediatric Porcine Model of Traumatic Brain Injury.

在小儿猪创伤性脑损伤模型中，白质损伤的成像与血浆和组织生物标志物相关。

DOI：
10.1089/neu.2022.0178
发表时间：
2023
期刊：
Journal of neurotrauma
影响因子：
4.2
作者：
Shin,SamuelS;Chawla,Sanjeev;Jang,DavidH;Mazandi,VanessaM;Weeks,MKatie;Kilbaugh,ToddJ
通讯作者：
Kilbaugh,ToddJ

Succinate prodrugs in combination with atropine and pralidoxime protect cerebral mitochondrial function in a rodent model of acute organophosphate poisoning.

DOI：
10.1038/s41598-022-24472-3
发表时间：
2022-11-25
期刊：
Scientific reports
影响因子：
4.6
作者：
Piel S;Janowska JI;Ward JL;McManus MJ;Jose JS;Starr J;Sheldon M;Clayman CL;Elmér E;Hansson MJ;Jang DH;Karlsson M;Ehinger JK;Kilbaugh TJ
通讯作者：
Kilbaugh TJ

The management of the poisoned patient using a novel emergency department-based resuscitation and critical care unit (ResCCU).