Project 5

项目5

• 批准号: 10491096
• 负责人: DAVID ANDREW WELLMAN
• 金额: $ 43.33万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491096
• 关键词: Affect; Animal Experimentation; Animal Experiments; Apnea; Area; Arousal; Brain Stem; Carbon Dioxide; Cell Nucleus; Cephalic; Clinical Trials; Collaborations; Data; Dilator; Disease; Drug Combinations; Effectiveness; Electroencephalography; Event; Functional disorder; Glean; Goals; Grant; Human; Impaired cognition; Individual; Intention; Light; Measures; Mediating; Methods; Motor; Muscarinics; Muscle; Muscle Tonus; Muscle hypotonia; Neurons; Norepinephrine; Obstructive Sleep Apnea; Outcome; Oxygen; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Phenotype; Physiological; Placebos; Prevention; REM Sleep; Research; Series; Serotonin; Serotonin Agonists; Serotonin Antagonists; Severities; Sleep; Sleep Apnea Syndromes; Sleep Disorders; Sleep Stages; Stimulant; Testing; Trazodone; Urinary Retention; Withdrawal; Xerostomia; airway muscle; airway obstruction; antagonist; atomoxetine; base; differential expression; druggable target; experience; gabapentin; human data; improved; indexing; inhibitor; member; non rapid eye movement; novel therapeutics; oxybutynin; pharynx muscle; prevent; receptor; receptor expression; respiratory; response; reuptake; sedative; serotonin receptor; side effect; trait; zolpidem

Abstract/ Summary: Project 5 OSA is a common and debilitating condition that currently has no effective pharmacotherapy. In the previous PPG, we identified a drug combination (atomoxetine + oxybutynin) that lowered the apnea-hypopnea index by 74% and raised the nadir oxygen saturation from 84% to 94%. Despite these encouraging results, some patients experienced antimuscarinic side effects from oxybutynin. Furthermore, subsequent mechanistic studies revealed that oxybutynin was acting primarily as a sedative (counteracting atomoxetine), rather than a pharyngeal muscle stimulant. Therefore, the goal of the current grant is to find a better sedative than oxybutynin to add to atomoxetine. This will be accomplished by first testing common, non-myorelaxing sedatives (Aim 1). Then, in Aim 2 we will test sedatives identified from Projects 1-4 that specifically block CO2- mediated arousals (but not CO2-mediated respiratory/pharyngeal muscle responses). As described in the other grants accompanying this PPG, Projects 2 and 4 are expected to identify serotonin subreceptors on parabrachial CGRP neurons (PBCGRP) that can be antagonized to prevent EEG arousal in response to elevated CO2. Additionally, Projects 3 and 4 will focus on identifying serotonin subreceptors on a separate group of parabrachial neurons (PBFoxP2) that could be manipulated pharmacologically to augment upper airway dilator tone. Of note, preliminary studies suggest that PBCGRP neurons are activated by a different subset of serotonin receptors than the PBFoxP2 neurons, thus allowing us to potentially target these two parabrachial regions independently. Therefore, Aim 2 will test specific serotonin agonists/antagonists, with or without atomoxetine (as necessary), to activate airway muscles without inducing arousals. Finally, in Aim 3 a one-month clinical trial will be performed on the most effective drugs emerging from Aims 1 and 2 (if no such drugs are found, then the original atomoxetine + oxybutynin combination will be studied). As the human component to this PPG, Project 5 will utilize the information gleaned from the animal experiments to build upon the exciting results of the previous PPG and move the field closer towards a potential pharmacotherapy for OSA.

摘要/总结：项目 5 OSA 是一种常见且令人衰弱的疾病，目前尚无有效的药物治疗方法。在之前的 PPG，我们发现了一种药物组合（阿托莫西汀 + 奥昔布宁），可降低呼吸暂停低通气指数 74% 并将最低氧饱和度从 84% 提高到 94%。尽管取得了这些令人鼓舞的结果，但一些 患者经历了奥昔布宁的抗毒蕈碱副作用。此外，后续机械 研究表明，奥昔布宁主要作为镇静剂（对抗阿托莫西汀），而不是镇静剂。 咽部肌肉兴奋剂。因此，当前拨款的目标是寻找一种比镇静剂更好的镇静剂。 奥昔布宁添加到阿托西汀中。这将通过首先测试常见的、非肌肉松弛的来完成 镇静剂（目标 1）。然后，在目标 2 中，我们将测试从项目 1-4 中确定的专门阻止 CO2 的镇静剂- 介导的唤醒（但不是二氧化碳介导的呼吸/咽肌反应）。如中所述 伴随本 PPG 的其他赠款，项目 2 和 4 预计将识别 5-羟色胺亚受体 臂旁 CGRP 神经元 (PBCGRP) 可以被拮抗，以防止响应升高的脑电图唤醒 二氧化碳。此外，项目 3 和 4 将重点识别一组单独的血清素亚受体。 臂旁神经元（PBFoxP2）可以通过药理学操作来增强上呼吸道扩张器 语气。值得注意的是，初步研究表明 PBCGRP 神经元是由不同的血清素子集激活的 受体比 PBFoxP2 神经元，因此使我们能够潜在地针对这两个臂旁区域 独立。因此，目标 2 将测试特定的血清素激动剂/拮抗剂，有或没有阿托西汀 （必要时），激活气道肌肉而不引起唤醒。最后，在目标3中进行为期一个月的临床试验 将针对目标 1 和 2 中出现的最有效的药物进行（如果没有找到此类药物，则 将研究原始阿托西汀+奥昔布宁组合）。作为该 PPG 的人力组成部分，Project 5 将利用从动物实验中收集的信息来构建令人兴奋的结果 先前的 PPG 并使该领域更接近 OSA 的潜在药物疗法。