CHOLINERGIC ASPECTS OF THE CAROTID BODY IN SLEEP APNEA

睡眠呼吸暂停中颈动脉体的胆碱能方面

• 批准号: 6527697
• 负责人: CHRISTOPHER P O'DONNELL
• 金额: $ 28.61万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6527697
• 关键词: acetylcholine; carotid body; cats; genetic regulation; genetic strain; genetic susceptibility; high performance liquid chromatography; immunocytochemistry; laboratory mouse; neurotransmitter transport; nicotinic receptors; northern blottings; nucleic acid sequence; pathologic process; plethysmography; polymerase chain reaction; polysomnography; receptor expression; receptor sensitivity; sleep apnea; statistics /biometry; voltage /patch clamp

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.

阻塞性睡眠呼吸暂停(OSA)的患病率在#年急剧上升 美国代表着严重的健康风险。其主要后果是 睡眠时的呼吸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，直到从睡眠中唤醒 恢复上呼吸道通畅。本项目建议确定 颈动脉小体感觉和反应重复性的机制 阻塞性睡眠呼吸暂停低氧血症间歇性发作。基于极其重要的 乙酰胆碱在颈动脉小体的兴奋性神经递质中的作用 低氧的化学转导，假设1)重复性 阻塞性睡眠呼吸暂停综合征间歇性低氧改变胆碱能转导通路 颈动脉小体，以及2)确定颈动脉小体的灵敏度 从基因上来说。具体目标1将检查重复的影响 睡眠间歇性低氧对一种新型小鼠颈动脉体部功能的影响 睡眠障碍呼吸的模型。《特定目标2》将调查 颈动脉乙酰胆碱和其他神经递质的释放模式 以及记录颈动脉窦神经活动，以响应 反复间歇性缺氧。《特定目标3》将使用免疫组织化学 和膜片钳分析来确定神经元烟碱型乙酰胆碱 受体(NAChRs)可以解释不同的缺氧反应 小鼠品系对缺氧的不同反应，并确定 反复间歇性低氧可上调nAChRs亚型的表达。