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.

与一般人群相比，退伍军人中阻塞性睡眠呼吸暂停(OSA)的发病率更高 退伍军人脊髓损伤的发生率进一步增加。因此，OSA 在退伍军人中是一个主要的健康问题。神经调节功能的调节 觉醒阈值(AT)、化学反射对低氧和高碳酸血症的敏感性(CS)及以上 呼吸道通畅是导致睡眠呼吸暂停加重的三个关键因素。这个 控制这些变量的确切神经调节器是个谜，但一种可能性是 5-羟色胺(5-HT)及其靶受体。因此，5-羟色胺神经元的可塑性可能是 治疗前后AT、CS、上呼吸道通畅率及最终呼吸稳定性的变化 脊髓损伤(SCI)动物。我们正在探索5-羟色胺在调节这些因素中的作用。 这会加剧完整和脊髓损伤小鼠的睡眠呼吸暂停。 如果不及时治疗，OSA可能会导致自主神经、心血管、神经认知和 代谢异常。在许多情况下，阻塞性睡眠呼吸暂停的治疗不会导致显著的 改进成果衡量标准。这种不足可能是减少的结果 持续气道正压(CPAP)治疗依从性和/或原因 除了那些与睡眠呼吸暂停直接相关的因素外，其他因素都有助于出现符合的共同睡眠呼吸暂停 病态。因此，提高CPAP依从性和/或直接提高CPAP依从性的创新疗法 影响不依赖CPAP治疗通常与阻塞性睡眠呼吸暂停相关的合并症 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是轻微的 间歇性低氧(MIH)引起胸壁和上呼吸道肌肉持续增加 人类的活动。这种持续的增长是一种称为长期呼吸可塑性的形式。 促进(LTF)。每天反复暴露于MIH，导致LTF的启动 呼吸道肌肉活动可增加上呼吸道的稳定性。与我的 实验室开发治疗睡眠呼吸暂停的创新疗法的任务增加了 稳定性最终可能会降低治疗阻塞性睡眠呼吸暂停综合征所需的CPAP。这一削减，加上 我们发表的研究结果表明，暴露在MIH中会提高觉醒阈值， 可以改善对CPAP的遵从性。提高合规性最终可能有助于 缓解与睡眠呼吸暂停有关的并发症。此外，除了改善CPAP之外， 依从性，大量研究表明，MIH对心血管有许多直接好处， 神经认知和代谢的影响。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)瞄准并缓解这些共同 与睡眠呼吸暂停有关的疾病。