Project 3

项目总结/摘要 - 项目 3 阻塞性睡眠呼吸暂停（OSA）是一种非常普遍的呼吸疾病，其特征是反复发作 仅在睡眠期间发生的部分和完全气道阻塞。 OSA 拥有重要的公众 健康负担，因为它与不良心血管、认知和疾病的发展有关 内分泌状况。与当前提案高度相关，以下内容重建气道通畅 阻塞性事件通常与睡眠唤醒（由脑电图激活定义）相关，从而导致 在许多情况下，睡眠碎片化、睡眠时间减少以及白天过度嗜睡。这种破坏 睡眠连续性被认为是阻塞性睡眠呼吸暂停 (OSA) 的许多病理后果的基础。无数失败 通过增强通气驱动来从药物角度治疗 OSA 的尝试受到了不必要的限制。 伴随通气增强的兴奋性增加。因此，开发方法 增强通气反应而不驱动皮质唤醒以应对高碳酸血症将是一个主要的方法 对 OSA 具有转化影响的进步。呼吸与皮质唤醒的详细回路 为了应对高碳酸血症——包括关键细胞群、它们的目标和它们的递质——仍然存在， 然而，不完全理解。这种知识差距阻碍了药理学的发展 治疗 OSA 的策略。此特定应用的目标是展示 CO2 响应性、 外侧新月臂旁核 (PBclFoxP2) 的谷氨酸能 FoxP2 神经元在驱动通气中的作用 独立于唤醒。中心假设是 PBclFoxP2 的选择前脑输入的激活 神经元将增强对高碳酸血症的通气反应，而不驱动皮质唤醒。理由 对于拟议的研究来说，成功区分了皮质与呼吸唤醒成分 高碳酸血症回路将使 OSA 的药物治疗策略成为可能，从而获得临床效果 受益于高碳酸血症的呼吸和唤醒反应的分离。强者引导 根据初步数据，我们的假设将通过追求四个具体目标来检验：1）识别并绘制突触前图 PBclFoxP2 神经元的前脑输入； 2）通过转录组分析，发现独特且“可成药”的 CO2 响应性 vlPB 细胞（包括 PBclFoxP2 细胞群）上的受体； 3）定义状态依赖 突触前前脑输入 PBcl 神经元的活动； 4) 确定信令是否来自定界， 神经化学定义的前脑输入可以增强对高碳酸血症的通气反应。方法 在智力和技术上都具有创新性，因为它强调前脑对 PBclFoxP2 神经元的输入 通气控制的背景，并且因为它采用了新开发的和 经过验证的技术方法。这项工作意义重大，因为它是连续过程中的几个关键步骤之一 预计将导致临床实用药物的鉴定和开发的研究 重建 OSA 患者气道通畅，且不会造成睡眠中断。

Project Summary/ Abstract- Project 3 Obstructive sleep apnea (OSA) is a highly prevalent breathing disorder characterized by recurrent episodes of partial and complete airway obstructions that occur exclusively during sleep. OSA poses a significant public health burden due to its being associated with the development of adverse cardiovascular, cognitive, and endocrine conditions. With high relevance to the current proposal, reestablishment of airway patency following an obstructive event is often associated with arousal from sleep (defined by activation of the EEG), resulting in sleep fragmentation, reduced sleep time, and excessive daytime sleepiness in many cases. This disruption of sleep continuity is thought to underlie many of the pathological consequences of OSA. Numerous failed attempts to treat OSA pharmacologically by enhancing ventilatory drive have been limited by unwanted increases in arousability that accompany ventilatory augmentation. Hence, development of methods to enhance ventilatory responses without driving cortical arousal in response to hypercapnia would be a major advance with translational impact for OSA. The detailed circuits underling respiratory versus cortical arousals in response to hypercapnia — including key cell groups, their targets and their transmitters — remains, however, incompletely understood. This knowledge gap has hampered the development of pharmacological strategies to treat OSA. The objective in this particular application is to demonstrate a role for CO2-responsive, glutamatergic FoxP2 neurons of the lateral crescent parabrachial nucleus (PBclFoxP2) in driving ventilation independent of arousal. The central hypothesis is that activation of select forebrain inputs to the PBclFoxP2 neurons will enhance the ventilatory response to hypercapnia without driving cortical arousals. The rationale for the proposed research is that successful demarcation of cortical versus respiratory arousal components of hypercapnia circuitry would enable pharmacological treatment strategies for OSA that derive their clinical benefit from the dissociation of the respiratory and arousal responses to hypercapnia. Guided by strong preliminary data, our hypotheses will be tested by pursuing four specific aims: 1) Identify and map presynaptic forebrain inputs to PBclFoxP2 neurons; 2) through transcriptome analysis, uncover unique and “druggable” receptors on CO2-responsive vlPB cells, including the PBclFoxP2 cell population; 3) define the state-dependent activity of presynaptic forebrain inputs to PBcl neurons; and 4) determine whether signaling from delimited, neurochemically-defined forebrain inputs can augment the ventilatory response to hypercarbia. The approach is intellectually and technically innovative because of its emphasis on forebrain inputs to PBclFoxP2 neurons in the context of ventilatory control, and because it employs a novel combination of newly developed and validated technical approaches. This work is significant because it is one of several key steps in a continuum of research that is expected to lead to the identification and development of a clinically practical drug that can reestablish airway patency in OSA patients without producing sleep disruption.