Central Respiratory Effects of Organophosphate Poisoning

有机磷中毒对中枢呼吸系统的影响

• 批准号: 7208947
• 负责人: ROMOLO J GASPARI
• 金额: $ 19.95万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-15 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7208947
• 关键词: Acetylcholinesterase; Acute; Acute respiratory failure; Animal Model; Anti-Cholinergics; Antidotes; Apnea; Applications Grants; Area; Atropine; Bilateral; Biology; Blood - brain barrier anatomy; Brain Stem; Breathing; Bromides; Bronchoconstriction; Cessation of life; Chemical Warfare Agents; Chemicals; Decerebration procedure; Diazepam; Dichlorvos; Diphenhydramine; Emergency Medicine; Equipment; GABA Agonists; Glycopyrrolate; Goals; Grant; Individual; Investigation; Laboratories; Massachusetts; Measures; Mediating; Medical Students; Medicine; Mentors; Neuraxis; Neurology; New York; Organophosphates; Output; Patients; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Physicians; Physiological; Poisoning; Program Development; Publications; Rate; Rattus; Research; Research Personnel; Research Training; Residencies; Respiration; Respiratory Insufficiency; Risk; Running; Sarin; Structure of phrenic nerve; Students; Testing; Toxicology; Training; Training Programs; Universities; Vagotomy; Ventilatory Depression; Washington; Writing; career; design; expectation; experience; medical schools; mortality; nerve agent; neurophysiology; neurotoxicology; organophosphate poisoning; prevent; programs; prophylactic; respiratory; sham surgery

DESCRIPTION (provided by applicant): This application contains a five-year research training program for the development of an academic career in neurophysiology and medicine. The candidate completed a Master's in Biology in 1993 at the George Washington University and an emergency medicine residency at the University of New York, Stony Brook Campus in 2000. Throughout his tenure as a graduate student, medical student, resident and attending, the applicant has continued to be involved in research. The described training program is designed to provide the candidate with the didactic and practical experience necessary for him to become an independent investigator in the fields of toxicology and neurophysiology. The scientific aims of this investigation focus on characterizing the central nervous system physiologic effects of organophosphate (OP) and nerve agents. Prior research has shown that patients poisoned with organophosphate poisons simply stop breathing. The PI has chosen Dr. David Paydarfar as a mentor for this project. As a practicing research physician at the University of Massachusetts, Dr. Paydarfar has extensive experience in respiration-related neurophysiology. The candidate's research efforts will focus on determining the mechanism by which organophosphates and nerve agents exert their effects on respiration. First, the candidate plans to test the hypothesis that death from acute organophosphate poisoning is caused by apnea due to acute loss of rhythmic output of the central respiratory oscillator in the brainstem. Phrenic nerve output will be determined in rats pretreated with glycopyrrolate undergoing either, sham surgery (controls), bilateral vagotomy, bilateral decerebration or both prior to OP with dichlorvos poisoning. A second set of hypotheses examine this same research question using an OP chemical warfare agent. A third hypothesis examines practical treatments for OP poisoning. Compounds suggested by preliminary research or prior publications will be systematically explored in the animal models described in Specific Aims 1 and 2. Gross mortality rates, phrenic nerve output and physiologic parameters will be measured in rats treated with compounds identified to be effective in OP poisoning. It is our expectation that by better understanding the mechanism of OP induced respiratory depression, prophylactic strategies to prevent mortality from OP in exposed individuals or those at high risk for exposure can be developed. The combination of training in the Departments of Neurology and Emergency Medicine at the University of Massachusetts Medical School provide an ideal setting and furthermore allow access to the facilities, equipment and expertise necessary to achieve the goals set forth in this proposal. The goal of the applicant is to become an independent researcher in the area of neurophysiology and neurotoxicology with the ability to run his own laboratory and write successful grant applications.

描述（由申请人提供）：本申请包含一个为期五年的研究培训计划，用于发展神经生理学和医学的学术生涯。申请人于 1993 年在乔治华盛顿大学完成了生物学硕士学位，并于 2000 年在纽约大学石溪分校完成了急诊医学住院医师实习。在他作为研究生、医学生、住院医师和主治医生的整个任期内，申请人继续参与研究工作。所述培训计划旨在为候选人提供成为毒理学和神经生理学领域的独立研究者所需的教学和实践经验。本研究的科学目的集中于表征有机磷酸盐 (OP) 和神经毒剂对中枢神经系统的生理效应。先前的研究表明，有机磷毒物中毒的患者只会停止呼吸。 PI 选择 David Paydarfar 博士作为该项目的导师。作为马萨诸塞大学的执业研究医师，Paydarfar 博士在呼吸相关神经生理学方面拥有丰富的经验。候选人的研究工作将集中于确定有机磷酸盐和神经毒剂对呼吸产生影响的机制。首先，候选人计划检验以下假设：急性有机磷中毒死亡是由于脑干中枢呼吸振荡器节律性输出急剧丧失而导致的呼吸暂停造成的。将在用格隆溴铵预处理的大鼠中测定膈神经输出，这些大鼠在敌敌畏中毒前进行假手术（对照）、双侧迷走神经切断术、双侧去大脑或两者都进行。第二组假设使用 OP 化学战剂来检验同一研究问题。第三个假设检验了 OP 中毒的实际治疗方法。初步研究或先前出版物建议的化合物将在具体目标 1 和 2 中描述的动物模型中进行系统探索。将在用经鉴定对 OP 中毒有效的化合物治疗的大鼠中测量总死亡率、膈神经输出和生理参数。我们期望，通过更好地了解OP引起呼吸抑制的机制，可以制定预防策略来预防暴露个体或高暴露风险人群因OP死亡。马萨诸塞大学医学院神经病学和急诊医学系的培训相结合，提供了理想的环境，而且还允许获得实现本提案中提出的目标所需的设施、设备和专业知识。申请人的目标是成为神经生理学和神经毒理学领域的独立研究人员，有能力经营自己的实验室并撰写成功的资助申请。