The candidate is a committed physician-scientist in Pediatric Critical Care, who aspires to become an independent investigator focused on developing novel ways to prevent brain injury and improve neurologic outcome after cardiac arrest. Neurologic disability among cardiac arrest survivors is common, costly, and severe. Cardiac arrest affects more than 350,000 people in the United States each year, and more than half of the survivors have substantial neurologic disabilities. The candidate's published preliminary data indicate that neuronal circuitry in the region of the thalamus responsible for sensation, attention and arousal is dysfunctional after cardiac arrest. The current proposal builds on this discovery and aims to determine the specific mechanism of thalamic circuit dysfunction after cardiac arrest (Aim 1). Furthermore, the affected thalamic circuit exerts a profound influence on the cerebral cortex both during development and in adulthood, suggesting that abnormal thalamic input after cardiac arrest contributes to disruption in cortical function among survivors. Hence, the proposal will investigate the impact of abnormal thalamic input on development of cortical function after cardiac arrest (Aim 2). The proposed experiments combine a cutting-edge, sophisticated and reproducible rodent model of cardiac arrest with modern techniques in sensory neurophysiology and neuroanatomy. The findings will be novel and important, as they will help design mechanism-based and age- appropriate treatment and rehabilitation strategies in cardiac arrest survivors. This Career Development Award builds on the candidate's extensive experience in systems neuroscience by augmenting his current skill set with world-class coursework in Computational Neuroscience, Imaging and Analysis of Defined Cell Populations. A well-developed, formal Career Development program complements the scientific classwork by requiring the candidate to master skills in grantsmanship and ethics, to demonstrate national expertise in his field through conference attendance and peer-reviewed publications, and to leverage the NIH-funded infrastructure for career development at Washington University School of Medicine. The training plan defines a specific timeline for classes, conference attendance, grant submissions, and progression to independence. The candidate has assembled and has already fully engaged a superb Scholarship Advisory Committee composed of internationally-recognized, funded physician-scientists with a broad range of expertise in neuroscience, molecular biology, development and physiology. The Institution, Washington University School of Medicine, has fully committed to supporting the candidate by protecting his research time, by providing the necessary laboratory space and financial resources, and by limiting his administrative, teaching and clinical responsibilities. Th proposed Career Development and Research plans, combined with the intellectual environment and institutional support at Washington University School of Medicine, will propel the candidate towards becoming an independent physician-scientist and a leader in Pediatric Critical Care.

Public Health Relevance

Neurologic disability among cardiac arrest survivors is common, costly and severe. A brain region called the thalamus, which controls awareness, attention and arousal, is often injured after cardiac arrest, and this injury likely contributes to neurologic disability in survivors. This project will identify specific mechanisms responsible for thalamic dysfunction after cardiac arrest and lead to novel treatment and rehabilitation strategies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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Gnadt, James W
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Washington University
Schools of Medicine
Saint Louis
United States
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Middleton, Jason W; Simons, Daniel J; Simmons, Jennifer W et al. (2017) Long-Term Deficits in Cortical Circuit Function after Asphyxial Cardiac Arrest and Resuscitation in Developing Rats. eNeuro 4:
Shoykhet, Michael; Middleton, Jason W (2016) Cardiac Arrest-Induced Global Brain Hypoxia-Ischemia during Development Affects Spontaneous Activity Organization in Rat Sensory and Motor Thalamocortical Circuits during Adulthood. Front Neural Circuits 10:68
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