Nitric Oxide and the Microcirculation in the Tibet Autonomous Region

这项研究的目标是发现这种独特的高原适应模式背后的机制，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在一起。它旨在发现1)微循环中红细胞速度和毛细血管结构对全身血流的比例贡献，2)微循环的这些特征(从血液中卸载氧气)对全球氧气输送的影响程度，3)血管扩张剂和血管生成因子对红细胞速度、毛细血管形态和氧气输送的贡献，以及4)形态和分子标记与候选基因中单核苷酸多态的关联。这一目标将通过在循环、微循环、分子和遗传水平上的同步测量来实现，使用一次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口循环中一氧化氮代谢产物异常大范围变异的后果。包括夏尔巴人在内的这群人以其在海拔地区生活和工作的能力而闻名，在那里，由于空气中的氧气量低于海平面，来自其他地方的人受到严重损害。这些反应可能是两万多年来自然选择磨练出来的进化反应，还是几年后的适应，这一问题将通过与成年后迁徙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问题，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基因更有效，是终生暴露的必要条件，还是任何人建立不同的生理稳态所需的一定暴露时间。填补我们在微循环中气体交换实际位置的氧气输送方面的知识空白，对于发现藏族人如何在严重的动脉缺氧情况下保持正常的氧气消耗，以及整合跨越人口、个人、器官系统、分子和遗传水平的科学发现，具有重要意义。了解西藏人对高海拔低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，人类生物变异的遗传和适应起源是什么，以及在低氧时期，可以用什么来帮助缺乏这种适应的人类？拟议研究的更广泛影响包括扩大与中国和西藏科学家、研究助理、志愿者和学生在从设计到发表的所有研究阶段的多学科合作伙伴关系。解决健康和疾病中对低氧的成功反应的差异对社会有益，因为如果发生低氧，反应可能是生死攸关的问题。目前，对于为什么一些人对缺氧反应成功，而另一些人则不能，人们几乎不了解。

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.