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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS048857-05
Application #
7777330
Study Section
NST-2 Subcommittee (NST)
Program Officer
Jett, David A
Project Start
2006-03-15
Project End
2011-09-28
Budget Start
2010-03-01
Budget End
2011-09-28
Support Year
5
Fiscal Year
2010
Total Cost
$204,495
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Emergency Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Gaspari, Romolo J; Paydarfar, David (2014) Pulmonary effects of intravenous atropine induce ventilation perfusion mismatch. Can J Physiol Pharmacol 92:399-404
Gaspari, Romolo J; Dunn, Courtney (2013) Dichlorvos exposure to the K├Âlliker-fuse nuclei is sufficient but not necessary for OP induced apnea. Neurotoxicology 39:132-7
Gaspari, Romolo J; Paydarfar, David (2012) Respiratory recovery following organophosphate poisoning in a rat model is suppressed by isolated hypoxia at the point of apnea. Toxicology 302:242-7
Dunn, Courtney; Bird, Steven B; Gaspari, Romolo (2012) Intralipid fat emulsion decreases respiratory failure in a rat model of parathion exposure. Acad Emerg Med 19:504-9
Gaspari, Romolo J; Paydarfar, David (2011) Dichlorvos-induced central apnea: effects of selective brainstem exposure in the rat. Neurotoxicology 32:206-14
Gaspari, Romolo J; Paydarfar, David (2009) Respiratory failure induced by acute organophosphate poisoning in rats: effects of vagotomy. Neurotoxicology 30:298-304
Gaspari, Romolo J; Paydarfar, David (2007) Pathophysiology of respiratory failure following acute dichlorvos poisoning in a rodent model. Neurotoxicology 28:664-71