CSRD Research Career Scientist Award Application

CSRD研究职业科学家奖申请

• 批准号: 10651710
• 负责人: Jason H. Mateika
• 金额: --
• 依托单位: JOHN D DINGELL VA 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: 2020-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651710
• 关键词: Adenosine; Animals; Apnea; Arousal; Award; Breathing; Cardiovascular system; Caring; Central Nervous System; Chest wall structure; Continuous Positive Airway Pressure; Coupled; Development; Diabetes Mellitus; Exposure to; Fatigue; Frequencies; Functional disorder; Genetic; Health; Human; Hypercapnia; Hypertension; Hypoxia; Incidence; Individual; Innovative Therapy; Knockout Mice; Laboratories; Legal patent; Limb structure; Link; Metabolic; Metabolic dysfunction; Modification; Motor; Mus; Neurocognitive; Neuromodulator; Neurons; Norepinephrine; Obstructive Sleep Apnea; Outcome; Outcome Measure; Pathway interactions; Patients; Population; Prevalence; Publishing; Recovery; Reflex action; Research; Respiratory Diaphragm; Role; Scientist; Serotonergic System; Serotonin; Severities; Sleep; Sleep Apnea Syndromes; Spinal Cord; Spinal cord injury; Spinal cord injury patients; Stroke; Therapeutic; Tryptophan 5-monooxygenase; United States; United States Department of Veterans Affairs; Vertebral column; Veterans; Work; airway muscle; career; comorbidity; compliance behavior; improved; improved outcome; improvement on sleep; military veteran; mouse model; neural; novel; pressure; receptor; respiratory; response; trait; ventilation

The prevalence of obstructive sleep apnea (OSA) is higher in Veterans compared to the general populace and the occurrence is increased further in Veterans with spinal cord injury. Thus, OSA is a major health concern in the Veteran population. Adjustments in the neural modulation of the arousal threshold (AT), chemoreflex sensitivity to hypoxia and hypercapnia (CS) and upper airway patency are three critical factors that contribute to exacerbation of sleep apnea. The exact neuromodulators that control these variables are enigmatic, but one possibility is serotonin (5HT) and its target receptors. Thus, plasticity of 5HT neurons may account for modifications in the AT, CS, upper airway patency and ultimately breathing stability in intact and spinal cord injured (SCI) animals. We are exploring the role of 5HT in modulating those factors that exacerbate sleep apnea in intact and SCI mice. If not treated promptly, OSA may result in autonomic, cardiovascular, neurocognitive and metabolic abnormalities. Treatment of OSA in many cases does not lead to significant improvements in outcome measures. This inadequacy may be a consequence of reduced treatment compliance with continuous positive airway pressure (CPAP) and/or because factors other than those directly linked to sleep apnea contribute to the presence of coincident co- morbidities. Consequently, innovative therapies that increase CPAP compliance and/or directly impact those co-morbidities typically associated with OSA independent of CPAP treatment could improve outcomes linked to sleep apnea. My laboratory has established that mild intermittent hypoxia (MIH) initiates sustained increases in chest wall and upper airway muscle activity in humans. This sustained increase is a form of respiratory plasticity known as long-term facilitation (LTF). Repeated daily exposure to MIH that leads to the initiation of LTF of upper airway muscle activity could lead to increased stability of the upper airway. In line with my laboratory's mandate to develop innovative therapies to treat sleep apnea, this increased stability could ultimately reduce the CPAP required to treat OSA. This reduction, coupled with our published findings which showed that exposure to MIH increases the arousal threshold, could lead to improved compliance with CPAP. Improved compliance could ultimately serve to mitigate those co-morbidities linked to sleep apnea. Moreover, in addition to improving CPAP compliance, numerous studies indicate that MIH has many direct beneficial cardiovascular, neurocognitive and metabolic effects. Thus, we are presently exploring if MIH can be used to both directly and indirectly (via improved CPAP compliance) target and mitigate those co- morbidities linked to sleep apnea.

与一般性相比，退伍军人的阻塞性睡眠呼吸暂停（OSA）的患病率更高 在脊髓损伤的退伍军人中，民众和发生的情况进一步增加。因此，OSA 在退伍军人人口中是主要的健康问题。调整神经调节 唤醒阈值（AT），化学反射对缺氧和高脑（CS）和上部的敏感性 气道通畅是三个关键因素，导致睡眠呼吸暂停加剧。这 控制这些变量的确切神经调节剂是神秘的，但一种可能性是 血清素（5HT）及其靶受体。因此，5HT神经元的可塑性可能解释 AT，CS，上呼吸道通畅性的修改以及完整的呼吸稳定性 脊髓受伤（SCI）动物。我们正在探索5HT在调节这些因素中的作用 在完整和科幻小鼠中加剧了睡眠呼吸暂停。 如果未迅速治疗，OSA可能会导致自主，心血管，神经认知和 代谢异常。在许多情况下，OSA的治疗不会导致重大 改进结果指标。这种不足可能是减少的结果 与连续气道压力（CPAP）和/或因素的治疗符合性的依从性 除了直接与睡眠呼吸暂停相关的呼吸暂停外，还有一致的共同存在 病态。因此，增加CPAP合规性和/或直接的创新疗法 影响那些通常与CPAP治疗无关的OSA相关的合并症 可以改善与睡眠呼吸暂停有关的结果。我的实验室已经确定了 间歇性缺氧（MIH）启动胸壁和上呼吸道肌肉的持续增加 人类的活动。这种持续增长是一种称为长期的呼吸可塑性形式 促进（LTF）。每天反复暴露于MIH，导致上部LTF的启动 气道肌肉活动可能导致上呼吸道的稳定性提高。与我一致 实验室制定创新疗法以治疗睡眠呼吸暂停的任务，这有​​所增加 稳定性最终可以减少治疗OSA所需的CPAP。这种减少，再加上 我们已发表的发现表明，接触MIH会增加唤醒阈值， 可能会改善对CPAP的遵守情况。提高合规性最终可能有助于 减轻与睡眠呼吸暂停相关的合并症。此外，除了改进CPAP 合规性，大量研究表明MIH具有许多直接有益的心血管 神经认知和代谢作用。因此，我们目前正在探索MIH是否可以习惯 直接和间接（通过提高CPAP依从性）目标，并减轻这些目标 与睡眠呼吸暂停有关的病态。