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

项目摘要 与毒物有关的事件导致超过45万人住院和75万人在急诊科就诊 访问，每年教育署访问的费用超过5.5亿美元。保守估计有5,000人死亡 在美国，每年有20,000起伤害是由线粒体中毒(例如一氧化碳、氰化物)造成的 (氰化物、硫化氢、磷化物)导致线粒体抑制，直接导致心脏骤停 和/或震惊。接触线粒体抑制剂的环境有多种，包括火灾、职业病 和工业接触、自杀以及潜在的空气、水和食物传播的恐怖主义毒剂，如 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。 并使用疗效不同的解毒剂治疗。导致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 由于知识上的重大差距，包括线粒体之间的关系，仍然居高不下 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基础 目标导向治疗的指标。我的长期目标是确定异常的特征特征 线粒体生物能量学及其在人体血细胞动力学中的应用 线粒体导向治疗的策略。我的中心假设，基于我的相关 在出版物和初步数据中发现的这笔赠款，是有相当大的变化与复杂的联系 急性中毒时的活性、ROS和动态反应。此外，血细胞可以被用来替代 受影响组织线粒体功能障碍的标志物。目前还没有直接的临床测试 以与急性病人护理相关的时间敏感型方式测量线粒体功能。这些实验 本申请中提出的将应用各种参数的测量或评估来定义 中毒患者分离的人血细胞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来指导人类血细胞的线粒体治疗 以可控的方式暴露于选定的线粒体毒物。建议进行这项研究的理由是 对线粒体生物能量学和运动学中出现的功能障碍有一个清晰的认识 对线粒体毒物的反应和正常线粒体功能的恢复 实施有效治理。

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.