Central Respiratory Effects of Organophosphate Poisoning

有机磷中毒对中枢呼吸系统的影响

• 批准号: 7385109
• 负责人: ROMOLO J GASPARI
• 金额: $ 20.11万
• 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/7385109
• 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; 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; experience; medical schools; mortality; nerve agent; neurophysiology; neurotoxicology; organophosphate poisoning; prevent; programs; prophylactic; respiratory; sham surgery

This application contains a five-year research training program for the development of an academic career in neurophysiology and medicine. The candidate completed a Masters 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 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 hope 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 PI is to become an independent researcher in the area of neurophysiology and neurotoxicology with the ability to run his own lab and write successful grant applications.

该应用程序包含一个为期五年的研究培训计划，用于学术发展 从事神经生理学和医学职业。该候选人于 1993 年在 乔治华盛顿大学和纽约大学斯托尼分校的急诊医学住院医师实习 2000 年，布鲁克校区。在他作为研究生、医学生、住院医师和住院医师的整个任期内 出席的申请人继续参与研究。所述训练计划的设计 为候选人提供必要的教学和实践经验，使他成为一名 毒理学和神经生理学领域的独立研究者。 这项研究的科学目的集中于表征中枢神经系统的生理学特征 有机磷（OP）和神经毒剂的作用。此前的研究表明，中毒患者 有机磷毒物只会导致呼吸停止。 PI 选择 David Paydarfar 博士作为导师 这个项目。作为马萨诸塞大学的一名执业研究医师，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酯的作用机制 神经毒剂对呼吸产生影响。首先，候选人计划检验以下假设： 急性有机磷中毒的死亡是由于呼吸节律性输出急剧丧失而导致的呼吸暂停造成的。 脑干中枢呼吸振荡器。将在经预处理的大鼠中测定膈神经输出 格隆溴铵接受假手术（对照）、双侧迷走神经切断术、双侧去脑术或两者同时进行 OP 之前使用敌敌畏中毒。第二组假设检验同一研究问题 使用 OP 化学战剂。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 目标 1 和 2 中描述的动物模型。总死亡率、膈神经输出和生理 将在用经鉴定对 OP 中毒有效的化合物治疗的大鼠中测量参数。这是 我们希望通过更好地了解 OP 引起的呼吸抑制预防性机制 预防暴露个体或暴露高风险人群因 OP 死亡的策略可以是 发达。 大学神经内科和急诊医学系的培训相结合 马萨诸塞州医学院提供了理想的环境，并允许使用这些设施， 实现本提案中规定的目标所需的设备和专业知识。 PI 的目标是 成为神经生理学和神经毒理学领域的独立研究员，并具有运行能力 他自己的实验室并撰写成功的资助申请。