Central Respiratory Effects of Organophosphate Poisoning

有机磷中毒对中枢呼吸系统的影响

• 批准号: 7029054
• 负责人: ROMOLO J GASPARI
• 金额: $ 19.65万
• 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/7029054
• 关键词: animal mortality; apnea; biological models; bioterrorism /chemical warfare; caffeine; decerebration; disease /disorder etiology; drug screening /evaluation; environmental exposure; environmental toxicology; laboratory rat; morphine; nerve gas; neurophysiology; neurotoxicology; nonhuman therapy evaluation; pathologic process; phosphorus compounds; phrenic nerve; quaternary ammonium compound; respiratory center dysfunction; respiratory function; respiratory insufficiency /failure; respiratory pharmacology; vagotomy; vagus nerve

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。候选人于1993年在乔治华盛顿大学获得生物学硕士学位，并于2000年在纽约大学斯托尼布鲁克校区获得急诊医学住院医师资格。在他作为一名研究生，医学生，居民和出席任期内，申请人继续参与研究。所描述的培训计划旨在为候选人提供必要的教学和实践经验，使其成为毒理学和神经生理学领域的独立研究者。本研究的科学目的集中在表征有机磷（OP）和神经毒剂的中枢神经系统生理效应。先前的研究表明，有机磷中毒的患者只是停止呼吸。PI已选择大卫Paydarfar博士作为该项目的导师。作为马萨诸塞州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在确定有机磷和神经毒剂对呼吸产生影响的机制。首先，候选人计划测试急性有机磷中毒死亡是由于脑干中央呼吸振荡器的节律输出急性丧失引起的呼吸暂停引起的假设。在敌敌畏中毒OP之前，将在接受假手术（对照）、双侧迷走神经切断术、双侧去大脑或两者的格隆溴铵预处理的大鼠中测定膈神经输出。第二组假设使用OP化学战剂来研究相同的研究问题。第三个假设检查OP中毒的实际治疗。初步研究或先前出版物建议的化合物将在特定目的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中毒有效的化合物处理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诱导呼吸抑制的机制，可以制定预防暴露个体或暴露高风险个体OP死亡的预防策略。马萨诸塞州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，并进一步允许获得实现本提案中规定的目标所需的设施、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，能够运行自己的实验室并撰写成功的资助申请。