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

• 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
• 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

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.

项目摘要 与中毒有关的事件导致45万多人住院，75万人急诊（艾德） 艾德诊症的费用每年超过5.5亿元。据保守估计， 在美国，每年有20，000例损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/或休克。暴露于线粒体抑制剂发生在各种环境中，包括火灾，职业 和工业接触，自杀和潜在的空气，水和食物传播的恐怖主义制剂， 武器化气体和液体目前的治疗是有限的，目前取决于支持性护理 以及使用不同有效性的解毒剂治疗。这些线粒体死亡的主要原因 抑制剂是循环休克和心脏骤停。尽管目前有治疗方法， 由于在知识方面存在重大差距，包括线粒体与 对急性线粒体中毒的反应功能障碍和缺乏足够的分子或细胞为基础的 目标导向治疗的指标。我的长期目标是识别出 线粒体生物能量学和动力学在人类血细胞以及应用一种新的药理学 脑靶向治疗策略。我的核心假设，是基于我的相关理论， 出版物和初步数据发现，在这个赠款，是有相当大的变化，复杂的联系， 活性，活性氧和动态响应急性中毒。血细胞也可以作为替代物 受影响组织的线粒体功能障碍的标志物。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 本申请中提出的方法将应用各种参数的测量或评估， 从中毒患者获得的分离的人血细胞中的线粒体生物能量学和动力学。我们 还将应用一种新的药理学策略，用于人类血细胞中的线粒体定向治疗 以受控的方式暴露于选择的线粒体毒素。拟议研究的基本原理是 发展一个清楚的理解，出现在线粒体生物能量学和运动功能障碍， 对线粒体毒物的反应和正常线粒体功能的恢复， 实施有效治疗。

项目成果

Topical nitroglycerin to detect reversible microcirculatory dysfunction in patients with circulatory shock after cardiovascular surgery: an observational study.

• DOI: 10.1038/s41598-022-19741-0
• 发表时间: 2022-09-10
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Greenwood, John C.;Talebi, Fatima M.;Jang, David H.;Spelde, Audrey E.;Tonna, Joseph E.;Gutsche, Jacob T.;Horak, Jiri;Acker, Michael A.;Kilbaugh, Todd J.;Shofer, Frances S.;Augoustides, John G. T.;Bakker, Jan;Brenner, Jacob S.;Muzykantov, Vladimir R.;Abella, Benjamin S.
• 通讯作者: Abella, Benjamin S.

Alterations in Mitochondrial Function in Blood Cells Obtained From Patients With Sepsis Presenting to an Emergency Department.

• DOI: 10.1097/shk.0000000000001208
• 发表时间: 2019-05
• 期刊: Shock (Augusta, Ga.)
• 作者: Jang DH;Orloski CJ;Owiredu S;Shofer FS;Greenwood JC;Eckmann DM
• 通讯作者: Eckmann DM

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

JMT 的研究概念部分：五年评估。

• DOI: 10.1007/s13181-019-00725-y
• 发表时间: 2019
• 期刊: Journal of medical toxicology : official journal of the American College of Medical Toxicology
• 作者: Jang,DavidH;Love,JenniferS;Mycyk,MarkB
• 通讯作者: Mycyk,MarkB

Severe Impairment of Microcirculatory Perfused Vessel Density Is Associated With Postoperative Lactate and Acute Organ Injury After Cardiac Surgery.

• DOI: 10.1053/j.jvca.2020.04.045
• 发表时间: 2021-01
• 期刊: Journal of cardiothoracic and vascular anesthesia
• 影响因子: 2.8
• 作者: Greenwood JC;Jang DH;Hallisey SD;Gutsche JT;Horak J;Acker MA;Bermudez CA;Zhou VL;Chatterjee S;Shofer FS;Kilbaugh TJ;Augoustides JGT;Meyer NJ;Bakker J;Abella BS
• 通讯作者: Abella BS

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

• DOI: 10.1371/journal.pone.0273349
• 发表时间: 2022
• 期刊: PloS one
• 影响因子: 3.7