CHOLINERGIC ASPECTS OF THE CAROTID BODY IN SLEEP APNEA

阻塞性睡眠呼吸暂停 (OSA) 的患病率在以下国家急剧增加 美国存在严重的健康风险。 主要后果是 睡眠期间气道阻塞会导致低氧血症，从而刺激 颈动脉体，导致呼吸动力增加，直到从睡眠中醒来 恢复上呼吸道通畅。 本项目建议确定 颈动脉体感知和响应重复的机制 OSA 间歇性低氧血症。 基于至关重要的 乙酰胆碱作为颈动脉体兴奋性神经递质的作用 缺氧的化学转导，假设 1）重复 OSA 的间歇性缺氧改变了胆碱能转导途径 颈动脉体，2) 确定颈动脉体的敏感性 从遗传上来说。 具体目标 1 将检查重复性的影响 睡眠期间间歇性缺氧对新型小鼠颈动脉体功能的影响 睡眠呼吸障碍模型。 具体目标 2 将调查 颈动脉释放乙酰胆碱和其他神经递质的模式 身体，以及记录颈动脉窦神经活动，以响应 反复间歇性缺氧。具体目标 3 将使用免疫组织化学 和膜片钳分析以确定神经元烟碱乙酰胆碱是否 受体（nAChR）可以解释不同的缺氧反应性 具有不同缺氧反应性的小鼠品系并确定是否 重复间歇性缺氧会上调 nAChR 亚型的表达。

The prevalence of Obstructive Sleep Apnea (OSA) is increasing dramatically in the U.S. representing a serious health risk. The primary consequence of airway obstruction during sleep is to cause hypoxemia which stimulates the carotid body, leading to increased respiratory drive until arousal from sleep restores upper airway patency. This project proposes to determine the mechanisms by which the carotid body senses and responds to the repetitive intermittent periods of hypoxemia in OSA. Based on the critically important role of acetylcholine as an excitatory neurotransmitter in the carotid body's chemotransduction of hypoxia, it is hypothesized 1) that the repetitive intermittent hypoxia of OSA alters cholinergic transduction pathways in the carotid body, and 2) that the sensitivity of the carotid body is determined genetically. Specific Aim 1 will examine the impact of repetitive intermittent hypoxia during sleep on carotid body function in a novel, murine model of sleep disordered breathing. Specific Aim 2 will investigate the pattern of acetylcholine and other neurotransmitter release from the carotid body, as well as recording carotid sinus nerve activity, in response to repetitive intermittent hypoxia. Specific Aim 3 will use immunohistochemical and patch clamp analyses to determine if neuronal nicotinic acetylcholine receptors (nAChRs) can account for differential hypoxic responsiveness between mouse strains with differential hypoxic responsiveness and determine whether repetitive intermittent hypoxia upregulates expression of subtypes of nAChRs.