Project 4 Chamberlin

项目 4 张伯伦

• 批准号: 9304307
• 负责人: NANCY L CHAMBERLIN
• 金额: $ 43.5万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9304307
• 关键词: Address; Affect; Air; Alternative Therapies; Apnea; Arousal; Atherosclerosis; Brain Injuries; Breathing; Carbon Dioxide; Cell Nucleus; Cholera Toxin Protomer B; Chronic; Clinical; Clozapine; Continuous Positive Airway Pressure; Data; Deposition; Dilator; Drops; Drowsiness; Drug Targeting; Electroencephalography; Engineering; Environmental air flow; Event; Fatty acid glycerol esters; Frequencies; Glutamates; Hypercapnia; Hypertension; Hypoxia; Impaired cognition; In Vitro; Innovative Therapy; Knowledge; Label; Link; Measures; Mediating; Metabolic syndrome; Methods; Microdialysis; Microinjections; Motor; Motor Neurons; Motor output; Mus; Muscarinic Acetylcholine Receptor; Muscarinics; Muscle; Muscle Tonus; Neurons; Nicotinic Receptors; Norepinephrine; Obstructive Sleep Apnea; Output; Oxides; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phase; Population; Presynaptic Terminals; Process; Public Health; Publishing; REM Sleep; Rabies virus; Recovery; Research; Signal Transduction; Sleep; Sleep Apnea Syndromes; Sleep Fragmentations; Source; Stimulus; Synapses; System; Therapeutic; Time; Tongue; Work; airway obstruction; brain circuitry; cholinergic; cholinergic neuron; cognitive function; design; experimental study; falls; genioglossus muscle; insight; neural circuit; neurochemistry; neuromechanism; noradrenergic; novel; pressure; presynaptic; prevent; receptor; respiratory; respiratory pharmacology; restoration; standard care; synaptic inhibition

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. .

摘要 阻塞性睡眠呼吸暂停是一个主要的公共卫生问题。小气道，通常因脂肪而进一步狭窄 当上呼吸道扩张肌（主要是 颏舌肌，GG）放松。GG张力的恢复对于每次阻塞事件的恢复是必要的。是 人们普遍认为，唤醒对于这一过程是必要的，但最近的数据表明，情况可能并非如此。 因此，对于许多阻塞性睡眠呼吸暂停综合症患者来说，睡眠期间增强GG活动可以阻止和逆转气道 梗阻发现一种可以实现这一目标的药理学试剂将是一个重大进展， 临床OSA管理。为了设计一种有效的药物治疗OSA，我们必须确定 能够增强GG活性及其对气道反应性的靶标或靶标组合 阻塞相关的刺激（主要是二氧化碳和负气道压力）在睡眠期间。最近令人兴奋的 证明REM期间阶段性呼吸GG活动的恢复（当它通常非常小或 缺失）通过将mAchR拮抗剂局部微透析到XII核中（Grace等， 2013）表明存在胆碱能神经元的系统，其防止对GG的与神经系统相关的驱动。 我们假设，抑制这一过程的药物将是治疗OSA。在这个项目中，我们建议 确定负责抑制GG的胆碱能神经元，并确定其机制， 行动上我们希望这将导致确定OSA的药理学靶点。 .