Project 3

项目3

• 批准号: 10491090
• 负责人: Patrick M Fuller
• 金额: $ 43.46万
• 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/10491090
• 关键词: Agonist; Agreement; Anatomy; Arousal; Automobile Driving; Brain Stem; Calcium; Carbon Dioxide; Cardiovascular system; Cell Nucleus; Cells; Clinical; Cognitive; Data; Development; Dissociation; Electroencephalography; Endocrine; Event; Excessive Daytime Sleepiness; Exposure to; FOXP2 gene; Glutamates; Goals; Heterogeneity; Hypercapnia; Image; In Situ Hybridization; In Vitro; Knowledge; Lateral; Lead; Maps; Measures; Methods; Molecular; Motor; Motor Neurons; Mus; Neurons; Obstructive Sleep Apnea; Pathologic; Pathway interactions; Patients; Pattern; Persons; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Photometry; Play; Population; Positioning Attribute; Prosencephalon; Public Health; Rabies; Recurrence; Regulation; Reporting; Research; Respiration Disorders; Response Latencies; Role; Signal Transduction; Sleep; Sleep Apnea Syndromes; Sleep Fragmentations; Sleep disturbances; Surveys; Synapses; Testing; Time; Work; airway obstruction; base; experimental study; improved; innovation; method development; neurochemistry; novel; parabrachial nucleus; photoactivation; presynaptic; receptor; receptor expression; respiratory; response; single-cell RNA sequencing; transcriptome; transcriptomics; translational impact; treatment strategy; ventilation

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.

项目概要/摘要-项目3 阻塞性睡眠呼吸暂停（OSA）是一种高度流行的呼吸障碍，其特征是反复发作的 仅在睡眠期间发生的部分和完全气道阻塞。OSA对公众造成了重大影响 健康负担，因为它与不良心血管，认知和 内分泌条件。与目前的建议高度相关， 阻塞性事件通常与从睡眠中唤醒（由EEG的激活定义）相关，导致 睡眠碎片化，睡眠时间减少，以及在许多情况下白天过度嗜睡。这种破坏 睡眠连续性被认为是OSA的许多病理后果的基础。无数失败 通过增强反射驱动来治疗OSA的尝试受到不希望的限制， 伴随着兴奋性增强的兴奋性增加。因此，开发方法， 增强对高碳酸血症的反应而不驱动皮质唤醒将是一个主要的 对OSA的转化影响。呼吸与皮层唤醒的详细回路 对高碳酸血症的反应--包括关键细胞群、它们的目标和它们的递质--仍然存在， 然而，并不完全理解。这种知识差距阻碍了药理学的发展， 治疗阻塞性睡眠呼吸暂停综合症的策略。在这个特定的应用中，目的是证明二氧化碳响应， 驾驶通气时外侧新月臂旁核（PBclFoxP 2）内FoxP 2能神经元的变化 独立于唤醒。中心假设是选择性前脑输入到PBclFoxP 2的激活 神经元将增强对高碳酸血症的呼吸反应而不驱动皮质觉醒。的理由 对于拟议中的研究是，成功划分皮层与呼吸唤醒成分， 高碳酸血症回路将使OSA的药理学治疗策略成为可能， 受益于高碳酸血症的呼吸和觉醒反应的分离。以强为导 初步数据，我们的假设将通过追求四个具体目标进行测试：1）识别和映射突触前 前脑输入到PBclFoxP 2神经元; 2）通过转录组分析，揭示独特的和“可药用”的 CO2-响应性vIPB细胞（包括PBclFoxP 2细胞群）上的受体; 3）定义状态依赖性 突触前前脑输入到PBc 1神经元的活动;和4）确定是否来自限定的， 神经化学定义的前脑输入可以增强对高碳酸血症的缓解反应。的方法 是智力和技术上的创新，因为它强调前脑输入PBclFoxP 2神经元， 由于它采用了一种新的组合， 经过验证的技术方法。这项工作是重要的，因为它是一个连续的几个关键步骤之一， 预期将导致鉴定和开发临床实用药物的研究， 在不影响睡眠的情况下重建OSA患者的气道通畅。