Project 4 Chamberlin

点击翻译按钮获取中文摘要

Abstract Obstructive sleep apnea is a major public health problem. Small airways, often further narrowed by fat deposits, are vulnerable to collapse during sleep when the upper airway dilator muscles (mainly the genioglossus, GG) relax. Restoration of GG tone is necessary for recovery from each obstructive event. It is widely believed that arousal is necessary for this process but recent data suggest that may not be the case. Thus, in many OSA patients augmentation of their GG activity during sleep would prevent and reverse airway obstruction. Discovery of a pharmacological agent(s) that could achieve this would be a major advance in clinical OSA management. In order to design an effective pharmacological treatment for OSA we must identify a target or combination of targets capable of augmenting GG activity and its responsiveness to airway obstruction-related stimuli (primarily CO2 and negative airway pressure) during sleep. A recent exciting demonstration of recovery of phasic respiratory GG activity during REM (when it is normally very small or absent) by local microdialysis of mAchR antagonists into the XII nucleus published last year (Grace et al., 2013) indicates that there is a system of cholinergic neurons that prevent respiratory-linked drive to the GG. We hypothesize that a drug that inhibits this process would be therapeutic for OSA. In this project we propose to identify the cholinergic neurons responsible for suppression of the GG and identify their mechanism of action. We expect this will lead to identification of pharmacological targets for OSA. .