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The Use of Blood Cells as a Biomarker in a Porcine Model of CO Poisoning with Evaluation of an Engineered Succinate-Prodrug

使用血细胞作为一氧化碳中毒猪模型中的生物标志物并评估工程琥珀酸前药

基本信息

批准号：
10276252
负责人：
DAVID H JANG
金额：
$ 69.73万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10276252
关键词：
Acute Address Affect Alternative Therapies Animal Model Animals Antidotes Applications Grants Biological Markers Blinded Blood Cells Brain Carbon Monoxide Carbon Monoxide Poisoning Carboxyhemoglobin Cardiac Cause of Death Cell physiology Cells Cerebrovascular Circulation Cerebrum Cities Clinical Complex Data Diagnostic Dose Electron Transport Engineering Ensure Evaluation Exhibits Exploratory/Developmental Grant for Diagnostic Cancer Imaging Exposure to Family suidae Fire - disasters Functional disorder Goals Health Heart Heart Injuries Hemoglobin Home Hour Human Hyperbaric Oxygen Hyperbaric Oxygenation Inflammation Injury Institution Intervention Intervention Trial Liquid substance Measures Metabolic Methods Mitochondria Modeling Monitor Morbidity - disease rate National Heart, Lung, and Blood Institute Nervous System Trauma Neurocognitive Neurocognitive Deficit Neurologic Organ Outcome Oxygen Oxygen Therapy Care Pathway interactions Patients Permeability Pharmacologic Substance Physiological Physiology Poisoning Predictive Value Prodrugs Production Prognosis Publications Randomized Reactive Oxygen Species Reproducibility Research Personnel Respiration Role Severities Severity of illness Specimen Succinates Survivors Sus scrofa System Testing Therapeutic Therapeutic Clinical Trial Tissues Toxic effect United States Work base career clinical application clinical biomarkers complex IV cytochrome c oxidase disability efficacy outcomes exhaust heart function heart metabolism mitochondrial dysfunction mortality novel porcine model pre-clinical preservation protein expression response success treatment effect treatment response treatment strategy

项目摘要

Our overarching goal is to advance understanding of mitochondrial mechanisms of carbon monoxide (CO) poisoning to develop diagnostics, therapeutics and clinical trials. CO poisoning remains a major cause of death and disability, affecting 50,000 people per year in the United States alone. Patients removed from fires or following exposure to car and home generator exhaust are placed on 100% oxygen and transferred to a facility with a hyperbaric oxygen (HBO) delivery system. Despite the availability of HBO therapy centers in most major cities, inherent delays in access to and initiation of therapy greatly limit efficacy. In fact, even with HBO oxygen therapy a substantial number of surviving patients exhibit permanent neurocognitive impairments. This highlights an urgent need for alternative therapy. In the present proposal, we propose to study novel antidotal therapies for CO poisoning, based on our ex vivo findings that the use of a succinate prodrug relieves partial CIV inhibition caused by CO poisoning. Another existing gap is the lack of effective biomarkers to gauge severity, prognosis, and response to treatment. While a carboxyhemoglobin level is readily available at most institutions, its use is limited only to confirm exposure with no predictive value. The three main objectives our proposal seeks to address are: (1) limited mechanistic understanding of the key role the mitochondria has in CO poisoning; (2) limitations of current biomarkers to gauge severity of disease and treatment response; (3) lack of treatment strategies that target mitochondrial dysfunction to mitigate long-term neurologic and cardiac disability. This project will define the mitochondrial pathways involved in CO poisoning using blood cells compared against brain and cardiac tissue in a porcine model of CO poisoning, furthering the mechanistic understanding of CO poisoning. Another important feature of this proposal is the evaluation of a new treatment strategy involving a mitochondrial prodrug with the potential to shift existing treatment paradigm. To achieve these objectives, a large animal trial in a porcine model of CO poisoning is proposed with the following aims: Aim 1 • To establish the mitochondrial mechanisms that contribute to the neurologic and cardiac injury that occur in CO poisoning and assess blood cell mitochondrial function as a potential liquid biomarker. Aim 2 • Randomized, blinded pre-clinical intervention trial in porcine models of CO poisoning to compare an engineered succinate prodrug to standard therapy of hyperbaric oxygen (HBO).

我们的首要目标是推进对碳的线粒体机制的理解