Validation of a Phenotype Model to Predict Response to Alternative OSA Treatments

项目摘要/摘要 阻塞性睡眠呼吸暂停(OSA)是一种常见的疾病，具有许多不利的心血管和 神经认知后果。然而，主要的治疗方法--气道正压治疗(PAP)--效果不佳。 因此，迫切需要新的治疗策略。 许多研究表明，阻塞性睡眠呼吸暂停综合征是由几个表型性状的相互作用引起的，包括 小气道是一种过度敏感的呼吸控制系统，在睡眠期间会减少咽部肌肉的活动， 以及对呼吸刺激的过早唤醒。在这次持续续签之前的前一次拨款中， 我们创造了测量这些特征的方法以及一个模型(称为“表型模型”)。 表示这些特征中的每一个对特定患者的OSA的相对贡献。我们相信这种模式可以 对于预测对PAP替代品的反应是有价值的。 此时，PAP的替代品(口腔矫治器、外科手术、舌下神经等器械 刺激等)结果不一致，而且没有针对阻塞性睡眠呼吸暂停综合征的药物治疗。怎么说呢- 呃，呼吸控制和觉醒因素，现在被认为具有致病作用，提供了位置。 潜在的新的(和未经测试的)药理靶点。这笔赠款的目的是验证预测的 OSA表型的能力，以及测试新的药物治疗单独和 与现有的PAP替代方案，如口腔矫治器疗法相结合。 在这笔赠款的目标1中，将使用前一笔赠款中开发的方法对患者进行“表型鉴定”。 然后我们将在模型上进行实验，例如，我们将用改变呼吸机的药物来治疗模型 控制敏感度和觉醒阈值。这些模拟的治疗将产生一个成功或 失败了。然后，我们将对患者进行治疗，看看模型预测是否正确。这个 将给予的治疗是乙酰唑胺(用于降低呼吸机控制敏感性)和埃索匹克隆。 (用于提高唤醒门槛)。这些药物将同时和单独给药。 因此，这笔赠款的一个创新部分是我们将结合药物以最大限度地提高疗效。目标2 将测试表型模型预测口腔矫治器治疗反应的能力。使用相同的程序 表型，然后对模型进行模拟处理以生成治疗预测，然后是前- 将使用周围式给药来观察预测是否正确。再就业的预测因素- 口腔矫治器疗法的效果仍然不佳，因此Aim 2填补了这一常见替代疗法的一个重要空白- 门槛。最后，目标3将测试表型模型预测“三联疗法”(乙酰唑拉-阿司匹林)反应的能力。 一种口腔矫治器)，我们的初步数据表明，这对AP有很强的疗效。 NEA严重程度在正确的“表型”。这项研究可能会带来令人振奋的新管理战略 奥萨。

PROJECT SUMMARY/ABSTRACT Obstructive Sleep Apnea (OSA) is a prevalent disorder with a number of adverse cardiovascular and neurocognitive consequences. However, the leading treatment, positive airway pressure (PAP), is poorly toler- ated by many individuals and thus the development new treatment strategies are critically needed. A number of studies indicate that OSA is caused by the interplay of several phenotypic traits, including a small airway, an oversensitive ventilatory control system, decreased pharyngeal muscle activity during sleep, and premature arousals to a respiratory stimulus. In the previous grant leading up to this continuing renewal, we created methods for measuring these traits as well as a model (termed the “phenotype model”) that illus- trates the relative contribution of each of these traits to a particular patient's OSA. We believe this model could be valuable for predicting response to PAP-alternatives. At this time, PAP alternatives (oral appliances, surgery, and other devices such as hypoglossal nerve stimulation, etc.) suffer from inconsistent results, and there is no pharmacological treatment for OSA. Howev- er, respiratory control and arousal factors, which are now recognized as having pathogenic roles, provide po- tential new (and untested) pharmacological targets. The objective of this grant is to validate the predictive power of OSA phenotyping, as well as to test the effectiveness of novel pharmacological treatments alone and in combination with existing PAP alternatives such as oral appliance therapy. In Aim 1 of this grant, patients will be “phenotyped” using the methods developed in the previous grant. We will then perform experiments on the model, e.g., we will treat the model with drugs that change ventilatory control sensitivity and arousal threshold. These simulated treatments will generate a prediction of success or failure. We will then administer the treatments to the patient to see if the model prediction was correct. The treatments that will be given are acetazolamide (for decreasing ventilatory control sensitivity) and eszopiclone (for raising the arousal threshold). These medications will be given simultaneously as well as individually. Thus, an innovative component of this grant is that we will combine medications to maximize efficacy. Aim 2 will test the phenotype model's ability to predict response to oral appliance therapy. The same procedure of phenotyping, followed by simulated treatment on the model to generate a treatment prediction, followed by ex- perimental administration of the treatment to see if the prediction was correct will be used. Predictors of re- sponse to oral appliance therapy remain poor, so Aim 2 fills an important gap in this common alternative treat- ment. Finally, Aim 3 will test the phenotype model's ability to predict response to “triple therapy” (acetazola- mide + eszopiclone + an oral appliance), which our preliminary data suggest can have a powerful effect on ap- nea severity in the right “phenotype”. This research could lead to exciting new management strategies for OSA.