Central Respiratory Effects of Organophosphate Poisoning

有机磷中毒对中枢呼吸系统的影响

• 批准号: 7873132
• 负责人: ROMOLO J GASPARI
• 金额: $ 5万
• 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 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7873132
• 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; Rattus; Research; Research Personnel; Research Training; Residencies; Respiration; Respiratory Insufficiency; Running; Sarin; Structure of phrenic nerve; Testing; Toxicology; Training; Training Programs; Universities; Vagotomy; Ventilatory Depression; Washington; Writing; career; design; experience; graduate student; high risk; 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.

此申请包含一个为期五年的研究培训计划，以发展一个学术 从事神经生理学和医学方面的工作。这位候选人于1993年在哈佛大学获得生物学硕士学位。 乔治·华盛顿大学和纽约大学斯通分校的急诊住院医师 2000年的布鲁克校园。在他作为研究生、医学生、住院医生和 参加申请者会议的人继续参与研究。设计了所描述的培训方案 为应聘者提供必要的教育和实践经验，使他成为一名 毒理学和神经生理学领域的独立研究员。 这项研究的科学目的在于描述中枢神经系统的生理学特征 有机磷(OP)和神经毒剂的影响。先前的研究表明，中毒的患者 有机磷中毒会让人停止呼吸。私家侦探已经选择大卫·佩达夫博士作为 这个项目。作为马萨诸塞大学的执业研究内科医生，佩达法尔博士 在呼吸相关神经生理学方面有丰富的经验。 候选人的研究工作将集中在确定有机磷的作用机制上 神经毒剂会对呼吸产生影响。首先，候选人计划检验这一假设 急性有机磷中毒的死亡是由呼吸暂停引起的，这是由于急性失去节律性输出 脑干中的中枢呼吸振荡器。大鼠膈神经输出量将被测定。 接受假手术(对照组)、双侧迷走神经切断术、双侧去大脑切断术或两者兼而有之的甘草酸脂 在实施敌敌畏中毒手术前。第二组假设考察了同样的研究问题。 使用一种OP化学战剂。第三种假说考察了OP中毒的实际治疗方法。 初步研究或以前的出版物建议的化合物将在 目标1和目标2中描述的动物模型：总死亡率、膈神经输出和生理 将对使用被确定为对OP中毒有效的化合物进行治疗的大鼠进行参数测量。它是 我们希望通过更好地了解OP引起呼吸抑制的机制来预防 预防暴露个人或暴露高危人群因OP死亡的策略可以是 发展起来的。 大学神经内科与急诊内科的结合培训 马萨诸塞州医学院提供了一个理想的环境，并进一步允许进入这些设施， 实现本提案所述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，具有运行能力 他自己的实验室，并成功地撰写了拨款申请。