Abnormal Mitochondrial Bioenergetic and Motility Signatures in Human Blood Cells as Indices of Acute Poisoning in Patients

人血细胞线粒体生物能和运动特征异常作为患者急性中毒的指标

基本信息

批准号：
10112290
负责人：
DAVID H JANG
金额：
$ 16.87万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-01-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112290
关键词：
Accident and Emergency department Acute Affect Age Air Antidotes Area Bioenergetics Biological Markers Blood Cells Blood Platelets Carbon Monoxide Cardiovascular system Cause of Death Cell Line Cell Respiration Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Characteristics Clinical Complex Cyanides Data Effectiveness Emergency Department patient Emergency Situation Emergency department visit Enrollment Environment Event Exhibits Exposure to Fire - disasters Functional disorder Funding Future Gases Generations Goals Grant Heart Arrest Hospitalization Hour Human Hydrogen Peroxide Hydrogen Sulfide Industrialization Injury Knowledge Link Liquid substance Measurement Measures Medicine Mentors Mentorship Methods Mitochondria Molecular Morbidity - disease rate Movement Occupational Occupational Exposure Patient Care Patients Peripheral Blood Mononuclear Cell Pharmacology Poison Poisoning Prodrugs Production Public Health Publications Research Research Personnel Research Training Resolution Respiration Resuscitation Resveratrol Science Shock Source Structure Succinates Suicide Supportive care Surrogate Markers Terrorism Testing Time Tissues Toxic effect Toxicology United States United States National Institutes of Health Work base cell motility clinical application complex IV cost cytochrome c effective therapy experimental study foodborne healthy volunteer improved indexing inhibitor/antagonist innovation medical specialties minimally invasive mitochondrial dysfunction mortality multidisciplinary novel patient population prospective response restoration skills treatment strategy waterborne weapons

项目摘要

Project Summary Poison-related incidents account for over 450,000 hospitalizations and 750,000 emergency department (ED) visits, with the yearly cost for ED visits exceeding $550 million. It is conservatively estimated that 5,000 deaths per year and 20,000 injuries in the US are due to mitochondrial poisons (e.g., carbon monoxide (CO), cyanide (CN), hydrogen sulfide (H2S), phosphides) resulting in mitochondrial inhibition leading directly to cardiac arrest and/or shock. Exposure to mitochondrial inhibitors occurs in a variety of settings, including fires, occupational and industrial exposures, suicide and potential air-, water- and food-borne terrorism agents such as weaponized gases and liquids. Treatment at this is time is limited and currently depends on supportive care and use of antidotal therapy of variable effectiveness. The primary cause of death to these mitochondrial inhibitors is circulatory shock and cardiac arrest. Despite currently available treatments, morbidity and mortality remains high due to significant gaps in knowledge, including the relationship between mitochondrial dysfunction in response to acute mitochondrial poisoning and the lack of adequate molecular or cell-based indices for goal-directed treatment. My long-term goal is to identify characteristic signatures of abnormalities in mitochondrial bioenergetics and dynamics in human blood cells as well as apply a new pharmacological strategy of mitochondrial-directed therapy. My central hypothesis, formulated on the basis of my relevant publications and preliminary data found in this grant, is that there are considerable changes in complex-linked activity, ROS and dynamics in response to acute poisoning. Also that blood cells may be used a surrogate marker of mitochondrial dysfunction of affected tissue. At this time there are no clinical tests that directly measure mitochondrial function in a time-sensitive manner relevant to acute patient care. The experiments proposed in this application will apply the measurement or assessment of various parameters defining mitochondrial bioenergetics and dynamics in isolated human blood cells obtained from poisoned patients. We will also apply a new pharmacologic strategy for mitochondrial directed treatment in human blood cells exposed to select mitochondrial poisons in a controlled manner. The rationale for the proposed research is develop a clear understanding of the dysfunction that appears in mitochondrial bioenergetics and motility in response to mitochondrial poisons and the restoration of normal mitochondrial function that occurs with implementation of effective treatment.

项目概要中毒相关事件导致超过 450,000 人住院治疗和 750,000 人急诊 (ED) 每年急诊就诊的费用超过 5.5 亿美元。保守估计有5000人死亡美国每年有 20,000 人受伤是由于线粒体毒物（例如一氧化碳 (CO)、氰化物 (CN)、硫化氢 (H2S)、磷化物）导致线粒体抑制，直接导致心脏骤停和/或震惊。暴露于线粒体抑制剂发生在多种环境中，包括火灾、职业和工业暴露、自杀以及潜在的空气、水和食物传播的恐怖主义制剂，例如武器化气体和液体。此时的治疗是有限的，目前依赖于支持性护理以及使用效果不同的解毒疗法。这些线粒体死亡的主要原因抑制剂是循环性休克和心脏骤停。尽管目前有可用的治疗方法，但发病率和死亡率由于知识上的巨大差距，包括线粒体之间的关系，仍然很高急性线粒体中毒导致的功能障碍以及缺乏足够的分子或细胞基础的目标导向治疗的指标。我的长期目标是识别异常的特征特征人类血细胞中的线粒体生物能量学和动力学，以及应用新的药理学线粒体定向治疗策略。我的中心假设是根据我的相关资料制定的在这笔赠款中发现的出版物和初步数据是，复杂链接发生了相当大的变化急性中毒反应的活性、活性氧和动态。血细胞也可以用作替代品受影响组织线粒体功能障碍的标志。目前还没有直接的临床试验以与急性患者护理相关的时间敏感方式测量线粒体功能。实验本申请中提出的将应用定义各种参数的测量或评估从中毒患者获得的分离人血细胞的线粒体生物能学和动力学。我们还将应用一种新的药理学策略，对人类血细胞进行线粒体定向治疗以受控方式暴露于选定的线粒体毒物。拟议研究的理由是对线粒体生物能量学和运动性中出现的功能障碍有一个清晰的了解对线粒体毒物的反应以及正常线粒体功能的恢复实施有效的治疗。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prophylaxis of mitochondrial dysfunction caused by cellular decompression from hyperbaric exposure.

预防高压暴露导致细胞减压引起的线粒体功能障碍。

DOI：
发表时间：
2020
期刊：
影响因子：
4.4
作者：
Ranganathan, Abhay;Owiredu, Shawn;Jang, David H;Eckmann, David M
通讯作者：
Eckmann, David M

A comparative analysis of National Institutes of Health research support for emergency medicine - 2008 to 2017.

美国国立卫生研究院急诊医学研究支持的比较分析 - 2008 年至 2017 年。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Jang, David H;Levy, Phillip D;Shofer, Frances S;Sun, Benjamin;Brown, Jeremy
通讯作者：
Brown, Jeremy

JMT's Research Concepts Section: a 5-Year Evaluation.

JMT 的研究概念部分：五年评估。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Jang, David H;Love, Jennifer S;Mycyk, Mark B
通讯作者：
Mycyk, Mark B

Protocol for the MicroRESUS study: The impact of circulatory shock and resuscitation on microcirculatory function and mitochondrial respiration after cardiovascular surgery.

MicroRESUS 研究方案：循环休克和复苏对心血管手术后微循环功能和线粒体呼吸的影响。

DOI：
发表时间：
2022
期刊：
影响因子：
3.7
作者：
Greenwood, John C;Talebi, Fatima M;Jang, David H;Spelde, Audrey E;Kilbaugh, Todd J;Shofer, Frances S;Acker, Michael A;Augoustides, John G T;Bakker, Jan;Meyer, Nuala J;Brenner, Jacob S;Muzykantov, Vladimir R;Abella, Benjamin S
通讯作者：
Abella, Benjamin S

Efficacy of methylene blue in an experimental model of calcium channel blocker-induced shock.

亚甲蓝在钙通道阻滞剂诱导休克实验模型中的功效。