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: 6233698
• 负责人: CHRISTOPHER P O'DONNELL
• 金额: $ 28.68万
• 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/6233698
• 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）的患病率在美国急剧增加， 美国面临严重的健康风险。 的主要后果 睡眠期间的气道阻塞会导致低氧血症， 颈动脉体，导致呼吸驱动增加，直到从睡眠中唤醒 恢复上呼吸道通畅 本项目旨在确定 颈动脉体感知和响应重复性的 阻塞性睡眠呼吸暂停综合征间歇性低氧血症。 基于至关重要的 乙酰胆碱作为兴奋性神经递质在颈动脉体 缺氧的化学转导，假设1）重复的 阻塞性睡眠呼吸暂停间歇性缺氧改变胆碱能信号转导通路 颈动脉体，以及2）确定颈动脉体的灵敏度 遗传的 具体目标1将审查重复的影响 睡眠中间歇性低氧对小鼠颈动脉体功能影响 睡眠呼吸障碍模型。 具体目标2将调查 乙酰胆碱和其他神经递质从颈动脉释放的模式 身体，以及记录颈动脉窦神经活动，以响应 反复间歇性缺氧Specific Aim 3将使用免疫组织化学 和膜片钳分析来确定神经元烟碱乙酰胆碱 受体（nAChRs）可以解释不同的缺氧反应之间 小鼠品系与差异缺氧反应，并确定是否 重复间歇性缺氧上调nAChR亚型的表达。