CSRD Research Career Scientist Award Application

CSRD研究职业科学家奖申请

• 批准号: 10426032
• 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/10426032
• 关键词: Adenosine; Animals; Apnea; Arousal; Award; Breathing; Cardiovascular system; Caring; 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; Lead; Limb structure; Link; Metabolic; Metabolic dysfunction; Modification; Motor; Mus; Neuraxis; Neurocognitive; Neuromodulator; Neurons; Norepinephrine; Obstructive Sleep Apnea; Outcome; Outcome Measure; Pathway interactions; Patients; Population; Prevalence; Publishing; Recovery; Research; Research Support; Respiratory Diaphragm; Role; Scientist; Serotonergic System; Serotonin; Severities; Sleep; Sleep Apnea Syndromes; Spinal; Spinal Cord; Spinal cord injury; Spinal cord injury patients; Stroke; Therapeutic; Time; Tryptophan 5-monooxygenase; United States; United States Department of Veterans Affairs; Veterans; Work; airway muscle; career; comorbidity; compliance behavior; improved; improved outcome; military veteran; mouse model; novel; pressure; receptor; relating to nervous system; 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.

阻塞性睡眠呼吸暂停（OSA）的患病率在退伍军人中高于一般人群。 脊髓损伤的发生率在退伍军人中进一步增加。因此，OSA 是退伍军人的主要健康问题。神经调制的调整 唤醒阈值（AT）、对低氧和高碳酸血症的化学反射敏感性（CS）和上限 气道通畅是导致睡眠呼吸暂停恶化的三个关键因素。的 控制这些变量的确切神经调质是谜，但一种可能性是， 5-羟色胺（5-HT）及其靶受体。因此，5 HT神经元的可塑性可能解释了 AT、CS、上气道通畅性和最终呼吸稳定性的改变， 脊髓损伤（SCI）动物。我们正在探索5 HT在调节这些因素中的作用， 加重了正常小鼠和脊髓损伤小鼠的睡眠呼吸暂停。 如果不及时治疗，OSA可能导致自主神经、心血管、神经认知和 代谢异常在许多情况下，OSA的治疗不会导致显著的 改善成果措施。这种不足可能是由于减少了 持续气道正压通气（CPAP）的治疗依从性和/或由于 除了那些直接与睡眠呼吸暂停有关的因素外， 病态因此，增加CPAP依从性和/或直接 影响那些通常与OSA相关的合并症，与CPAP治疗无关 可以改善与睡眠呼吸暂停相关的结果。我的实验室已经证实 间歇性缺氧（MIH）引起胸壁和上气道肌肉的持续增加 人类的活动。这种持续的增加是呼吸可塑性的一种形式，被称为长期 促进（LTF）。每天重复暴露于MIH，导致上LTF启动 气道肌肉活动可导致上气道的稳定性增加。符合我 实验室的任务是开发创新的疗法来治疗睡眠呼吸暂停，这增加了 稳定性可以最终减少治疗OSA所需的CPAP。这种减少，加上 我们发表的研究结果表明，暴露于MIH会增加唤醒阈值， 可以改善CPAP的依从性。改善遵守情况最终可有助于 减轻与睡眠呼吸暂停相关的并发症。此外，除了改进CPAP 顺应性，许多研究表明，MIH有许多直接有益的心血管， 神经认知和代谢影响。因此，我们目前正在探索MIH是否可以用于 直接和间接（通过改善CPAP合规性）针对和减轻这些共同影响， 与睡眠呼吸暂停有关的疾病