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

建议研究的目的：* 本计划旨在更好地了解调节生理适应高海拔缺氧的机制。总体目标是进行人体综合脑血管生理学研究，旨在阐明高海拔适应期间睡眠中断的机制，并制定和实施改善高海拔工人睡眠和日间功能的方法。科学方法摘要：* 该计划将在卡尔加里大学和我们的工业合作伙伴泰克资源公司的矿场进行。卡尔加里的研究将调查志愿者大脑中发生的变化，在清醒和睡眠期间，当动脉血气紧张度以预定义和完全控制的方式改变时，持续时间从几分钟到48小时不等。已经构建了一个腔室，其中环境PO 2可以通过添加氮气或氧气来调节，并且其中环境PCO 2可以通过添加或去除二氧化碳来调节，以分别防止呼吸性水肿和酸中毒。这个房间在加拿大是独一无二的，也是第一个用于进行研究的房间，主要集中在人类睡眠期间对缺氧的长期脑血管适应。在矿场进行的研究将调查在休息时、清醒时和睡眠时脑血管对长时间暴露于缺氧的反应的适应性，方法是研究矿工在适应海拔（海拔3,000米以上;智利Quebrada Blanca矿）和在低海拔工作的矿工（即，对照组）（高地谷铜矿，坎卢普斯BC）。随着这项计划的展开，研究神经血管耦合机制的新方法（结合研究血流和神经元活动的技术）将随之而来。工作的新奇和预期意义：* 我们的实验室在加拿大是独一无二的，其创新功能包括：i）在短时间和长时间内准确和连续地控制动脉PCO 2和PO 2的复杂技术，ii）能够以高时间分辨率同时和连续地测量呼吸，脑血流量，血压和心率的变化（逐呼吸、逐心跳），和iii）描述脑血流、血压、心率和呼吸响应于人体缺氧而表现的方式的动态数学模型。此外，我们与Teck Resources（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。这种伙伴关系是作为NSERC互动赠款（2011年）的一部分发起的，以解决与高海拔采矿相关的一些生理挑战。这项研究计划将使动脉气体控制的复杂技术的使用，以研究调节脑血管，呼吸和心血管控制在人类的机制。研究环境独特，非常适合高海拔生理学研究。拟议的计划将产生重大影响，有助于推进我们对人类脑血管生理学的认识，以及随之而来的缺氧和高原适应。预计该研究将强调睡眠不佳对白天表现的影响，该研究可适用于世界各地的重型设备操作员，无论睡眠不足的原因和工人的地理位置如何。最后，该计划将汇集生物医学研究的跨学科团队，并将在加拿大和国外的大学环境和行业内为HQP提供出色的培训机会。

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.