Mechanisms underlying adaptations to the hypoxia of high altitude: neurovascular regulation, sleep and cognitive function

适应高海拔缺氧的机制：神经血管调节、睡眠和认知功能

• 批准号: RGPIN-2014-05554
• 负责人: Poulin, Marc
• 金额: $ 2.91万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=687860
• 关键词: Mechanisms; underlying; adaptations; hypoxia; altitude

OBJECTIVES OF THE PROPOSED RESEARCH PROGRAM:*This program aims to better understand the mechanisms that regulate the physiological adaptations to the hypoxia of high altitude. The overall objective is to conduct human integrative cerebrovascular physiology studies, which aim to elucidate the mechanisms, by which sleep is disrupted during acclimatization to high altitude, and to develop and implement ways of improving sleep and daytime function in high altitude workers.**SUMMARY OF SCIENTIFIC APPROACH:*The program will be conducted at the University of Calgary and at mine sites of our industrial partner, Teck Resources. The studies in Calgary will investigate the alterations that occur in the brain of volunteers, during wakefulness and during sleep, when the arterial blood gas tensions are altered in a pre-defined and fully controlled manner for a period ranging from minutes to 48 hours. A chamber has been built in which the ambient PO2 can be adjusted by adding either nitrogen or oxygen and in which the ambient PCO2 can be adjusted by adding or removing carbon dioxide to prevent respiratory alkalosis and acidosis, respectively. This chamber is unique in Canada and the first of its kind used to carry out investigations that focus predominantly on long-term cerebrovascular adaptations to hypoxia during sleep in humans. Studies at the mine sites will investigate the adaptive nature of the cerebrovascular responses to prolonged exposure to hypoxia at rest, while awake and during sleep, by studying miners during acclimatization to altitude (> 3,000m above sea level; Quebrada Blanca mine, Chile) and miners who work at low altitude (i.e., control group)(Highland Valley Copper mine, Kamloops BC). As this program unfolds, novel approaches to study the mechanisms of neurovascular coupling (combining techniques to study both blood flow and neuronal activity) will ensue.**NOVELTY AND EXPECTED SIGNIFICANCE OF THE WORK: *Our laboratory is unique in Canada, and its innovative features include i) sophisticated technique to control arterial PCO2 and PO2 accurately and continuously over short and prolonged periods, ii) the ability to make simultaneous and continuous measurements of the ensuing changes in respiration, cerebral blood flow, blood pressure and heart rate with high temporal resolution (breath-by-breath, beat-by-beat), and iii) dynamic mathematical models that describe the way in which cerebral blood flow, blood pressure, heart rate, and respiration behave in response to hypoxia in humans. Further, we have established important and necessary collaborations with Teck Resources (a mining company that operates copper mines in Canada and Chile). This partnership was initiated as part of an NSERC Interaction grant (2011) to address some of the physiological challenges associated with high altitude mining. This research program will enable the use of sophisticated techniques in arterial gas control to study the mechanisms that regulate cerebrovascular, respiratory, and cardiovascular control in humans. The research environments are unique and ideally suited for studies of high altitude physiology. The proposed program will have a major impact in helping advance our knowledge of human cerebrovascular physiology and the adaptations that ensue with exposure to hypoxia and altitude. It is anticipated that the research will highlight the impact of poor sleep on daytime performance, which can be applied to operators of heavy equipment everywhere regardless of the cause of sleep loss and the geographic location of the workers. Finally, this program will bring together an interdisciplinary team in biomedical research and will provide outstanding training opportunities for HQP both within the university environment and industry in Canada and abroad.

拟议研究计划的目标：*该计划旨在更好地了解调节生理适应高原低氧的机制。总体目标是进行人类综合脑血管生理学研究，旨在阐明在适应高原期间睡眠中断的机制，并开发和实施改善高原工人睡眠和白天功能的方法。**科学方法总结：*该计划将在卡尔加里大学和我们的工业合作伙伴Teck Resources的矿场进行。卡尔加里的这项研究将调查志愿者大脑在清醒和睡眠期间发生的变化，当动脉血气压力以预先定义的和完全可控的方式变化时，时间从几分钟到48小时不等。已经建立了一个小室，其中可以通过添加氮气或氧气来调节环境PO2，可以通过添加或去除二氧化碳来调节环境PCO2，以分别防止呼吸性碱中毒和酸中毒。这个实验室在加拿大是独一无二的，也是第一个用于进行研究的，主要集中在人类睡眠期间对低氧的长期脑血管适应。矿场研究将通过研究适应海拔的矿工(海拔3000米；智利Quebrada Blanca矿)和在低海拔作业的矿工(即对照组)(高原山谷铜矿，卑诗省坎卢普斯)，研究矿工在休息、清醒和睡眠时对长期暴露于低氧环境的脑血管反应的适应性。随着这一计划的开展，研究神经血管耦合机制的新方法将随之而来。**工作的新颖性和预期意义：*我们的实验室在加拿大是独一无二的，其创新特征包括i)在短时间和长时间内准确和连续地控制动脉二氧化碳分压和氧分压的复杂技术，ii)能够以高时间分辨率(逐次呼吸、逐次跳动)同时和连续地测量随后发生的呼吸、脑血流量、血压和心率的变化，以及iii)描述大脑血流量方式的动态数学模型，人类的血压、心率和呼吸对低氧有反应。此外，我们还与泰克资源(一家在加拿大和智利经营铜矿的矿业公司)建立了重要和必要的合作关系。这一伙伴关系是作为NSERC互动赠款(2011)的一部分发起的，目的是解决与高海拔采矿相关的一些生理挑战。这项研究计划将使在动脉气体控制方面使用尖端技术来研究调节人类脑血管、呼吸和心血管控制的机制成为可能。研究环境独特，非常适合高海拔生理学研究。拟议的计划将对帮助我们提高对人类脑血管生理学以及随后暴露在低氧和高原下的适应能力的知识产生重大影响。预计这项研究将突出睡眠不佳对白天表现的影响，这一点适用于世界各地的重型设备操作员，无论导致睡眠损失的原因和工人的地理位置如何。最后，该项目将汇聚一支生物医学研究的跨学科团队，并将在加拿大国内外的大学环境和行业内为HQP提供出色的培训机会。