Project 4

项目4

• 批准号: 10674888
• 负责人: Veronique VanderHorst
• 金额: $ 44.91万
• 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/10674888
• 关键词: Adult; Anatomy; Arousal; Atherosclerosis; Biological Assay; Blood; Brain; Brain Stem; Breathing; Calcium; Carbon Dioxide; Cardiovascular Physiology; Cardiovascular system; Cell Nucleus; Continuous Positive Airway Pressure; Dependence; Development; Dilator; Drops; Drowsiness; Dyspnea; EGR2 gene; Electroencephalography; Excessive Daytime Sleepiness; Genetic; HTR2A gene; Heart Rate; Hypercapnia; Hypertension; Imaging Device; Impaired cognition; In Vitro; Intervention; Maps; Measures; Mediating; Medical; Metabolic; Metabolic syndrome; Modeling; Molecular; Motor; Motor Activity; Movement; Mus; Muscle; Muscle Tonus; Neurons; Nucleus solitarius; Obstructive Sleep Apnea; Oxygen; Population; Property; Rabies virus; Receptor Signaling; Recombinant adeno-associated virus (rAAV); Recurrence; Respiratory Acidosis; Respiratory Diaphragm; Role; Sensory; Serotonin; Site; Sleep; Sleep Apnea Syndromes; Sleep Fragmentations; Slice; Stress; Synapses; System; Tachycardia; Therapeutic; Tidal Volume; Tissues; Transgenic Organisms; Validation; Visualization; Wakefulness; Work; combat; comorbidity; designer receptors exclusively activated by designer drugs; falls; genioglossus muscle; improved; in vivo; innovation; middle age; neural; optogenetics; pharmacologic; preBotzinger complex; pressure; prevent; programs; respiratory; response; serotonin 7 receptor; serotonin receptor; tool; transcriptomics; vasoconstriction; ventilation

Project Summary Obstructive sleep apnea (OSA) is a debilitating condition leaving 14%-49% of middle-aged adults with excessive daytime sleepiness and impaired cognitive, metabolic, and cardiovascular functioning. Treatments beyond the often poorly tolerated CPAP remain limited, despite this unmet medical need. This Program Project seeks to identify new intervention points in neural brain circuits to combat OSA. In OSA, the activity of muscles that keep the airway open drops leading to airway collapse and impeded ventilation. Tissue and blood oxygen levels fall and carbon dioxide (CO2) levels rise (hypercapnia). This leads to an intensification of breathing movements, meant to improve ventilation, but which only worsen the airway collapse by generating negative pressure. Once a threshold of hypercapnia is reached, the brain arouses, rapidly leading to robust airway opening, resumption of ventilation, and return to sleep. This OSA cycle occurs many times per night, fragmenting sleep and inflicting autonomic surges underlying vasoconstriction and tachycardia that drive much of the comorbidity. Our Program seeks to identify neural brain circuits to optimize the activity of muscles that keep the airway open and to augment breathing (Respiratory Augmentation) without arousing the brain. In Project 4, we focus on the serotonergic neuronal system in the lower brainstem in mice, leveraging our team’s recent discovery of two genetically distinct subtypes of serotonergic neurons each critical for a robust ventilatory response to hypercapnia, yet each acting on largely distinct components of the neural respiratory arousal circuit. The subtype denoted Egr2-Pet1 increases respiratory drive by connections to centers that measure pCO2 and that mediate arousal, whereas the second subtype, denoted Tac1-Pet1, sends connections to motor centers that control airway dilation and inspiration. By modulating these subtypes separately it may be possible to a) optimize airway dilator tone to avoid airway closure, b) optimize ventilation to avoid exacerbation of airway closure, c) optimize EEG arousal threshold to reduce sleep fragmentation, and d) avoid cardiovascular stress. In Aim 1, we will study how Egr2-Pet1 and Tac1-Pet1 populations modulate each of these different functions during wake, sleep, and arousal, enabled via intersectional chemogenetic tools in combination with a Repeated-CO2-Arousal model for OSA, while measuring diaphragm and airway dilator muscle activity, brain activity, heart rate, and respiratory rate and depth. In Aim 2, we will use in vivo and in vitro optogenetic and calcium imaging tools to determine circuit nodes to which Egr2-Pet1 and Tac1-Pet1 neurons functionally connect, relevant for airway dilation, ventilation, and arousal. In Aim 3, we will visualize the circuit nodes from which Tac1-Pet1 and Egr2-Pet1 neurons receive input. Throughout, we will query response dependence on serotonin receptors, relevant for pharmacological strategies in OSA. Collectively, results from this work have the potential to transform our understanding of and approaches to prevent OSA.

项目摘要 阻塞性睡眠呼吸暂停（OSA）是一种使人衰弱的状况，其中14％-49％的中年成年人患有 白天嗜睡过多，认知，代谢和心血管功能受损。治疗 除了通常耐受性不佳的CPAP之外，仍然有限，请执行这种未满足的医疗需求。这个程序项目 试图确定神经脑回路中的新干预点以对抗OSA。在OSA中，肌肉的活动 这样可以使气道开放，导致气道崩溃并阻碍通风。组织和血氧 水平降低，二氧化碳（CO2）水平升高（高碳酸盐）。这导致呼吸的强化 动作，旨在改善通风，但由于产生负面，气道崩溃更糟 压力。一旦达到了高碳酸脂蛋白的阈值，大脑唤醒，迅速导致强大的气道 开放，恢复通风并重新入睡。这个OSA周期每晚多次发生， 裂缝的睡眠和促进很多动力的血管收缩和心动过速的自主潮流 合并症。我们的计划旨在识别神经脑电路，以优化肌肉的活动 保持气道打开并增加呼吸（呼吸增加），而不会引起大脑。在 项目4，我们专注于小鼠下部脑干的血清能神经元系统，利用我们的团队的 最近发现了两个普遍不同的血清素能神经元的亚型，每个神经元对于强大的 对高碳酸血症的通气反应，但每种反应都在神经呼吸的很大不同的成分上作用 唤醒电路。亚型表示EGR2-PET1通过与中心连接增加呼吸驱动器 测量PCO2和媒体唤醒，而第二个亚型表示TAC1-PET1，发送连接 控制控制气道词典和灵感的汽车中心。通过分别调节这些亚型 可能a）优化气道扩张器音调以避免气道关闭，b）优化通风以避免加剧 气道关闭，c）优化脑电图唤醒阈值以减少睡眠破碎，d）避免 心血管应激。在AIM 1中，我们将研究EGR2-PET1和TAC1-PET1种群如何调节每个 这些在唤醒，睡眠和唤醒期间通过交叉化学发生工具在 与OSA的重复CO2-Arousal模型结合，同时测量隔膜和气道扩张器 肌肉活动，大脑活动，心率以及呼吸频率和深度。在AIM 2中，我们将使用体内和 体外光遗传学和钙成像工具，用于确定EGR2-PET1和TAC1-PET1的电路节点 神经元在功能上连接，与气道扩散，通风和唤醒有关。在AIM 3中，我们将可视化 TAC1-PET1和EGR2-PET1神经元从中接收输入的电路节点。在整个过程中，我们会查询 对5-羟色胺受体的反应依赖性与OSA中的药物策略有关。共同 这项工作的结果有可能改变我们对预防OSA的理解和方法。