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: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=567238
• 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.

拟建研究项目目的：本项目旨在更好地了解调节高原缺氧生理适应的机制。本研究的总体目标是开展人类综合脑血管生理学研究，旨在阐明高原适应过程中睡眠中断的机制，并制定和实施改善高原工人睡眠和白天功能的方法。科学方法概述：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区进行。卡尔加里的研究将调查志愿者在清醒和睡眠期间发生的变化，当动脉血气紧张在一段时间内以预先定义的和完全控制的方式改变时，从几分钟到48小时。通过添加氮气或氧气调节环境PO2，通过添加或去除二氧化碳调节环境PCO2，分别防止呼吸性碱中毒和酸中毒。这个腔室在加拿大是独一无二的，也是同类中第一个用于开展主要关注人类睡眠期间对缺氧的长期脑血管适应的调查。在矿区的研究将通过研究适应海拔的矿工（智利Quebrada Blanca矿海拔3000米以上）和在低海拔工作的矿工（即对照组）（加拿大坎卢普斯省Highland Valley Copper mine），研究在休息时、清醒时和睡眠时长时间暴露于缺氧下的脑血管反应的适应性。随着该计划的展开，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。工作的新颖性和预期意义：我们的实验室在加拿大是独一无二的，它的创新特点包括：1)精密的技术，可以在短时间和长时间内精确和连续地控制动脉二氧化碳分压和二氧化碳分压；2)能够同时和连续地测量呼吸、脑血流量、血压和心率的变化，具有高时间分辨率（每次呼吸、每次心跳）；iii)动态数学模型，描述脑血流量、血压、心率和呼吸对人类缺氧的反应方式。此外，我们与泰克资源公司（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。这一合作关系是作为NSERC互动资助（2011年）的一部分发起的，旨在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能够用于研究调节人类脑血管、呼吸和心血管控制的机制。研究环境独特，非常适合研究高原生理学。该计划将对促进我们对人类脑血管生理学的了解以及暴露于缺氧和高海拔环境后的适应能力产生重大影响。预计该研究将强调睡眠不足对白天工作表现的影响，这可以应用于任何地方的重型设备操作员，而不考虑睡眠不足的原因和工人的地理位置。最后，该项目将汇集一个跨学科的生物医学研究团队，并将在加拿大和国外的大学环境和行业中为HQP提供优秀的培训机会。