Project 3

项目摘要/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的呼吸道阻塞。OSA引起了公众的广泛关注 健康负担，因为它与不利的心血管、认知和 内分泌状况。与目前的提议高度相关，在以下情况下重建呼吸道通畅 阻塞性事件通常与从睡眠中唤醒(由脑电激活定义)有关，导致 睡眠支离破碎，睡眠时间减少，在许多情况下白天过度困倦。这种扰乱 睡眠的连续性被认为是阻塞性睡眠呼吸暂停的许多病理后果的基础。无数次失败 通过增强通风驱动力进行药物治疗阻塞性睡眠呼吸暂停综合征的尝试受到了不必要的限制。 伴随着呼吸增强而增加的唤醒能力。因此，方法的发展是为了 在不刺激皮质觉醒的情况下增强对高碳酸血症的呼吸反应将是一个主要的 提高OSA的翻译影响力。呼吸与大脑皮层觉醒相关的详细回路 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传递体--仍然存在， 然而，并不完全理解。这种知识鸿沟阻碍了药理学的发展。 治疗阻塞性睡眠呼吸暂停综合征的策略。该特定应用中的目标是展示二氧化碳响应的作用， 驱动通气时臂旁外侧新月核谷氨酸能FoxP2神经元的变化 不受唤醒的影响。中心假设是PBclFoxP2的选定前脑输入被激活 神经元将增强对高碳酸血症的呼吸反应，而不会驱动大脑皮层的觉醒。其基本原理是 对于拟议的研究来说，成功地划分大脑皮层和呼吸觉醒成分 高碳酸血症回路将使阻塞性睡眠呼吸暂停综合征的药物治疗策略成为可能，从而获得临床上的 从对高碳酸血症的呼吸和觉醒反应的解离中受益。以Strong为指导 初步数据，我们的假设将通过追求四个具体目标来验证：1)识别和映射突触前 前脑对PBclFoxP2神经元的输入；2)通过转录组分析，发现独特的和可下药的 二氧化碳反应的vlPB细胞上的受体，包括PBclFoxP2细胞群体；3)定义状态依赖的 突触前脑传入PBCL神经元的活动；以及4)决定来自定界的、 神经化学定义的前脑输入可以增强对高碳酸血症的呼吸系统反应。该方法 是智力和技术上的创新，因为它强调前脑对PBclFoxP2神经元的输入 通风控制的背景下，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 有望导致识别和开发一种临床实用药物的研究，这种药物可以 在不造成睡眠中断的情况下，重建阻塞性睡眠呼吸暂停综合征患者的呼吸道通畅。

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.