Project 5

项目5

• 批准号: 10674892
• 负责人: DAVID ANDREW WELLMAN
• 金额: $ 42.88万
• 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/10674892
• 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; Pharmacotherapy; Pharyngeal structure; Phenotype; Physiological; Placebos; Predisposition; 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; differential expression; druggable target; experience; gabapentin; human data; improved; indexing; inhibitor; member; non rapid eye movement; novel therapeutics; oxybutynin; pharmacologic; 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/摘要：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。在上一个 ppg，我们确定了一种药物组合（阿托西汀 + oxybutynin），该药物通过 74％，将Nadir氧饱和度从84％提高到94％。尽管结果令人鼓舞，有些 患者经历了羟丁肽的抗毒性副作用。此外，随后的机理 研究表明，羟丁氏蛋白主要起作用是镇静剂（应对原子氨酸），而不是一个镇静剂 咽肌肉刺激剂。因此，目前赠款的目标是找到比 羟丁蛋白添加到原子苷中。这将通过首先测试常见的非毛线轴来实现 镇静剂（目标1）。然后，在AIM 2中，我们将测试从1-4项目中确定的镇静剂，这些镇静剂专门阻止CO2- 介导的唤醒（但不是CO2介导的呼吸/咽肌反应）。如 伴随该PPG的其他赠款，项目2和4有望在 可拮抗以防止出现升高的脑电图，可防止脑电图响应于升高 二氧化碳。此外，项目3和4将专注于在单独的组上识别5-羟色胺亚受体 可以在药理上操纵以增强上空气道扩张仪的副神经元（PBFOXP2） 语气。值得注意的是，初步研究表明PBCGRP神经元被不同的5-羟色胺激活 受体比PBFOXP2神经元，从而使我们能够瞄准这两个止痛区 独立。因此，AIM 2将测试特定的5-羟色胺激动剂/拮抗剂，有或没有原子氨酸 （必要时），激活气道肌肉而不会引起唤醒。最后，在AIM 3中，一个月一个月的临床试验 将对目的1和2出现的最有效药物进行（如果找不到这样的药物，则 将研究原始的原子苷 +氧化丁物蛋白组合）。作为该PPG的人类组成部分，项目 5将利用从动物实验中收集的信息来建立令人兴奋的结果 先前的PPG并将现场移动到OSA的潜在药物治疗。