Project 5

项目5

基本信息

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
项目类别：
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

项目摘要

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，以防止脑电图唤醒响应升高二氧化碳。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 神经元由不同的血清素子集激活受体比 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。