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.

与普通人相比，退伍军人中阻塞性睡眠呼吸暂停 (OSA) 的患病率更高 在患有脊髓损伤的退伍军人中，这种情况的发生率进一步增加。因此，OSA 是退伍军人群体的一个主要健康问题。神经调节的调整 唤醒阈值 (AT)、对缺氧和高碳酸血症 (CS) 的化学反射敏感性以及上 气道通畅是导致睡眠呼吸暂停恶化的三个关键因素。这 控制这些变量的精确神经调节剂是个谜，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、上呼吸道通畅性和最终呼吸稳定性的改变 脊髓损伤（SCI）动物。我们正在探索 5HT 在调节这些因素中的作用 会加剧完整小鼠和 SCI 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，OSA 的治疗不会带来显着的效果。 成果衡量指标的改进。这种不足可能是由于减少 持续气道正压通气 (CPAP) 的治疗依从性和/或因素 除了那些与睡眠呼吸暂停直接相关的因素之外，还导致同时存在的共同因素 发病率。因此，提高 CPAP 依从性和/或直接 影响那些通常与 OSA 相关的合并症，独立于 CPAP 治疗 可以改善与睡眠呼吸暂停相关的结果。我的实验室已经确定温和的 间歇性缺氧（MIH）引发胸壁和上呼吸道肌肉持续增加 在人类中的活动。这种持续的增加是呼吸可塑性的一种形式，称为长期 便利化（LTF）。每天重复接触 MIH，导致上颌 LTF 的发生 气道肌肉活动可以提高上气道的稳定性。符合我的 实验室的任务是开发治疗睡眠呼吸暂停的创新疗法，这增加了 稳定性最终可以减少治疗 OSA 所需的 CPAP。这种减少，再加上 我们发表的研究结果表明，接触 MIH 会增加唤醒阈值， 可以提高 CPAP 的依从性。提高合规性最终可以有助于 减轻与睡眠呼吸暂停相关的并发症。此外，除了改善 CPAP 依从性，大量研究表明 MIH 对心血管有许多直接有益的作用， 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）目标并减轻这些共同的影响 与睡眠呼吸暂停有关的疾病。