MECHANISMS OF HUMAN CEREBRAL BLOOD FLOW REGULATION IN ACUTE AND LIFELONG HYPOXIA IN LOWLANDERS AND INDIGENOUS POPULATIONS

背景：相对于其大小，大脑是人体中最依赖氧气的器官，但许多病理生理和环境过程可能导致或导致其氧气供应的妥协。因此，研究急性和/或重复缺氧应激或高海拔下的大脑是研究急性和慢性低氧血症对脑血管功能影响的合适模型。有充分的文献证明，脑血流量增加，以应对缺氧刺激的严重程度，在人类通过血管舒张。虽然暴露于急性、常压和低压（如高海拔）缺氧时脑血流量（CBF）的增加似乎足以维持脑氧输送，但目前对这些潜在机制的了解很少，特别是在人类中。尽管缺氧的生理压力，一些土著居民在高海拔地区存活了几千年，这表明他们已经适应了缺氧的条件。人类适应高海拔缺氧的成功模式有三种：安第斯模式、西藏模式和埃塞俄比亚模式。因此，急性和长时间的上升或居住在高海拔地区，代表了对大脑的复杂刺激，其性质尚不清楚，特别是考虑到动脉酸碱平衡和代谢的持续改变和补偿。通过结合复杂的黄金标准脑测量技术，该研究计划的目标分为两个实际主题，基于人类对急性和长期（主题一）和终身（主题二）缺氧的不同反应，解决以下具体问题：问题1：急性缺氧诱导脑血管舒张和维持脑氧输送的主要机制是什么？问题2：长时间缺氧诱导脑血管舒张和维持脑氧输送的主要机制是什么？问题3：在不同的高海拔适应表型中，脑血流调节是否有不同的进化？意义：解决本提案中概述的新问题将丰富我们对急性和/或终身缺氧条件下CBF基本机制的理解。由于现代化和移民正在改变各地高地居民的传统生活方式和暴露于环境的模式，因此对土著高海拔和潜水人口继续进行实地调查是迫切需要的。揭示低氧适应的生理基础将有助于了解与低氧耐受性有关的血液学和其他适应，并且有助于解释人类进化到其环境的过程。

BACKGROUND: 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 a compromise to its oxygen supply. As such, studying the brain under acute and/or repetitive 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 in response to the severity of hypoxic stimuli in humans via vasodilation. Although the increases in cerebral blood flow (CBF) upon exposure to acute and normo- and hypobaric (e.g., high altitude) hypoxia seem 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 Indigenous 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, Tibetan and Ethiopian pattern. Acute and prolonged ascent or residency at high altitude, thus represents a complex stimulus to the brain, the nature of which is not well understood, particularly in light of sustained alterations and compensations in arterial acid-base balance and metabolism. By combining sophisticated gold-standard brain measurement techniques, this goal of this program of research is split into two practical themes based on the divergent human responses to acute and prolonged (theme one) and lifelong (theme two) hypoxia that address the following specific questions: QUESTION 1: What are the main mechanism(s) by which acute hypoxia induces cerebral vasodilation and maintenance of cerebral oxygen delivery? QUESTION 2:What are the main mechanism(s) by which prolonged hypoxia induces cerebral vasodilation and maintenance of cerebral oxygen delivery?. QUESTION 3: Has CBF regulation differentially evolved amongst the different phenotypes of adaptation to high altitude? SIGNIFICANCE: Addressing the novel questions outlined in this proposal will enrich our understanding of the fundamental mechanisms governing CBF in conditions of acute and/or, and lifelong hypoxia. Continuing fieldwork in Indigenous high altitude and diving populations is urgent since modernization and migration are changing the traditional ways of life and patterns of exposure to the environment among highlanders everywhere. Uncovering the physiological basis of hypoxic adaptation will inform understanding of hematological and other adaptations involved in hypoxia tolerance and will moreover facilitate explication of the processes by which humans have evolved to their environments.