Mechanisms and quantification of human cerebral blood flow regulation in acute and chronic hypoxia

急慢性缺氧时人脑血流调节机制及定量

• 批准号: RGPIN-2015-03766
• 负责人: Ainslie, Philip
• 金额: $ 3.57万
• 依托单位: University of British Columbia
• 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=689781
• 关键词: Mechanisms; quantification; human; cerebral; blood

Relative to its size, the brain is the most oxygen-dependent organ in the body, but many pathophysiological and environmental processes may either cause or result in an interruption to its oxygen supply. As such, studying the brain under hypoxia stress or at high altitude is an appropriate model to investigate both acute and chronic effects of hypoxemia on cerebrovascular function. It has been well documented that cerebral blood flow increases, especially in the brainstem region, in response to the severity of hypoxic stimuli in humans via vasodilation. Although the increases in cerebral blood flow upon exposure to normo- and hypobaric (e.g., high altitude) hypoxia seems to be adequate to maintain cerebral oxygen delivery, the current understanding of these underlying mechanisms is poor, especially in humans. Despite the physiological stress of hypoxia, several human populations have survived for millennia at high altitudes, suggesting they have adapted to hypoxic conditions. There are three successful patterns of human adaptation to high-altitude hypoxia: Andean ("classic adaptation" erythrocytosis with arterial hypoxemia); Tibetan (normal hemoglobin concentration with arterial hypoxemia); and the recently identified Ethiopian pattern (normal hemoglobin concentration will only modest levels of arterial hypoxemia). The mechanisms of human cerebral blood flow regulation across each of these populations have not been compared - their description would clarify current ambiguities in our understanding of cerebral blood flow regulation in health and provide potential targets for maximizing cerebral oxygenation in disease. By combining sophisticated gold-standard brain measurement techniques, with and without pharmacological interventions, this goal of this program of research is split into two practical themes based on the divergent human responses to acute (theme one) and chronic (theme two) hypoxia that address the following general goals: 1) to quantify the mechanisms by which hypoxia can alter cerebral blood flow at both sea level and high altitude; and 2) explore if the control mechanisms that regulate cerebral blood flow are altered in chronic successful patterns of human adaptation to high-altitude hypoxia in Andean, Tibetan and Ethiopian populations. These goals will be addressed in >8 different experimental interventions at both sea level and high altitude. Characterization of these relationships between oxygen, cerebral blood flow and cerebral metabolism, and their respective importance on brain homeostasis is a fundamental step toward raising our understanding of brain physiology to that of other body systems. Uncovering the physiological basis of hypoxic adaptation will both inform understanding of hematological and other adaptations involved in hypoxia tolerance and form the basis of novel methods of treating conditions of pathological brain hypoxia.**

相对于其大小，大脑是体内最依赖氧的器官，但许多病理生理和环境过程可能导致或导致其氧供应中断。因此，研究缺氧应激或高海拔下的脑是研究低氧血症对脑血管功能的急性和慢性影响的合适模型。 已经充分证明，脑血流量增加，特别是在脑干区域，通过血管舒张响应于人类中缺氧刺激的严重性。尽管暴露于常压和低压时脑血流量增加（例如，尽管高海拔）缺氧似乎足以维持脑氧输送，但目前对这些潜在机制的理解很差，尤其是在人类中。尽管存在缺氧的生理压力，但一些人类种群在高海拔地区生存了数千年，这表明他们已经适应了缺氧条件。人类对高海拔低氧的适应有三种成功模式：安第斯（“经典适应”红细胞增多伴动脉低氧血症）;西藏（血红蛋白浓度正常伴动脉低氧血症）;以及最近发现的埃塞俄比亚模式（血红蛋白浓度正常伴动脉低氧血症）。这些人群中的人类脑血流调节机制尚未进行比较-它们的描述将澄清我们对健康脑血流调节的理解中目前的模糊性，并为疾病中最大化脑氧合提供潜在目标。通过结合先进的金标准大脑测量技术，有和没有药物干预，这项研究计划的目标分为两个实际的主题，根据不同的人类对急性脑缺血的反应。（主题一）和长期（主题二）缺氧，主要目的是：1）量化缺氧改变海平面和高海拔脑血流的机制; 2）探索在安第斯山脉、西藏和埃塞俄比亚人群中，人类对高海拔缺氧的慢性成功适应模式中，调节脑血流的控制机制是否发生了改变。这些目标将在海平面和高海拔地区的8个以上不同的实验干预措施中实现。氧气，脑血流量和脑代谢之间的这些关系的表征，以及它们各自对脑内稳态的重要性，是提高我们对脑生理学的理解到其他身体系统的基本步骤。揭示缺氧适应的生理基础将有助于了解缺氧耐受性中涉及的血液学和其他适应，并形成治疗病理性脑缺氧状况的新方法的基础。