Nitric Oxide and the Microcirculation in the Tibet Autonomous Region

这项研究的目的是发现适应高海拔的独特模式的机制，这种模式将非常高的全身血流量与非常高的一氧化氮水平结合起来。 它被设计成发现1）微循环中红细胞速度和毛细血管结构对全身流动的比例贡献，2）微循环的那些特征（其中氧气从血液中卸载）影响整体氧气输送的程度，3）血管扩张剂和血管生成因子对红细胞速度、毛细血管形态、和氧输送和4）形态和分子标记与候选基因中的单核苷酸多态性的关联。 这一目标将通过同时测量循环、微循环、分子和遗传水平来实现，使用一次性案例研究设计来分析西藏自治区日喀则地区贝南县藏族人群中循环一氧化氮代谢物异常大范围变化的后果。 这个人口，其中包括夏尔巴人，以其在海拔高度生活和工作的能力而闻名，而其他地方的人由于空气中的氧气含量低于海平面而受到严重损害。 这些反应是否可能是经过2万多年自然选择磨练的进化反应，还是几年后达到的适应，这个问题将通过与成年后迁移的高海拔汉族移民样本进行比较来解决。 在高海拔地区生活的能力的生物学基础是一个重要的长期存在的问题，并可能为人们适应极端环境的各种方式提供线索。 例如，某些形式的人类基因是否比其他形式更有效，是否需要终生暴露，或者是否需要一定的暴露时间才能建立不同的生理稳态。填补我们在微循环气体交换的实际部位的氧气输送知识的差距，对于发现藏人在严重动脉缺氧的情况下如何正常耗氧，以及整合整个人口、个体、器官系统、分子和遗传水平的科学发现，都具有重要意义。 了解西藏人对高海拔缺氧的独特适应模式将有助于回答核心问题：适应是如何进化的，它们发生的速度有多快，人类生物学变异的遗传和适应性起源是什么，以及在缺氧期间，什么可以用来帮助缺乏这种适应的人类？拟议研究的更广泛影响包括在从设计到出版的所有研究阶段扩大与中国和西藏科学家、研究助理、志愿者和学生的多学科合作。 解决健康和疾病中对缺氧的成功反应的变化范围对社会有益，因为如果缺氧发生，反应可能是生死攸关的问题。 目前还不清楚为什么有些人对缺氧反应成功，而另一些人却没有。

The goal of the study is to discover the mechanisms underlying the distinctive pattern of adaption to high altitude that couples very high systemic blood flow with extraordinarily high levels of nitric oxide. It is designed to discover 1) the proportional contributions to systemic flow of red blood cell velocity and capillary architecture in the microcirculation, 2) the extent to which those features of the microcirculation, where oxygen is offloaded from the blood, influence global oxygen delivery, 3) the contribution of vasodilators and angiogenic factors to red cell velocity, capillary morphology, and oxygen delivery and 4) the association of morphological and molecular markers with single-nucleotide polymorphisms in candidate genes. The goal will be achieved with simultaneous measurements at the circulatory, microcirculatory, molecular, and genetic levels using a one-shot case study design to analyze the consequences of the exceptionally large range of variation in circulating nitric oxide metabolites in the Tibetan population of Benam County, Xigatse Prefecture, Tibet Autonomous Region. This population, which includes Sherpas, is famous for its ability to live and work at altitudes where people from the elsewhere are severely impaired owing to less than sea-level amounts of oxygen in the air. The question of whether the responses are likely to be evolutionary responses honed by natural selection over more than 20,000 years or acclimatizations reached after a few years will be addressed by comparison with a sample of high-altitude Han Chinese migrants who migrated as adults. The biological basis of the ability to live at high altitudes is an important long-standing question and may offer clues to various ways people adapt to extreme environments. For examples, are certain forms of human genes more effective than others, is a lifetime of exposure a requirement, or is a certain exposure time required for anyone to establish a different physiological homeostasis. Filling the gap in our knowledge of oxygen delivery at the actual site of gas exchange in the microcirculation is important for discovering how Tibetans have normal oxygen consumption despite profound arterial hypoxia and for integrating scientific discoveries across the population, individual, organ system, molecular and genetic levels. Understanding the distinctive Tibetan pattern of adaptation to high-altitude hypoxia will help answer central questions: how do adaptations evolve, how fast do they occur, what are the genetic and adaptive origins of human biological variation, and what can be used to assist humans who lack this adaptation during times of hypoxia? The broader impact of the proposed research includes expanded multidisciplinary partnerships with Chinese and Tibetan scientists, research assistants and volunteers and students at all research phases from design through publication. Addressing the range of variation in successful responses to hypoxia in health and disease benefits society since the response can be a matter of life and death if hypoxia occurs. At present there is little understanding of why some people respond successfully to hypoxia and others do not.