High-altitude environments and spleen function in humans

一些生活在世界山区的人类适应了高海拔的低氧条件，特别是在登山活动中。该项目的主要目标是研究人类脾脏在高海拔地区运动耐受性中的作用，并评估这种压力如何影响在高海拔地区生活和运动了数千年的人群的脾脏功能。脾脏调节循环的红细胞，从而调节血液的携氧能力；在其他物种（如潜水哺乳动物、赛马）中，研究表明，当氧气是一个限制因素时，脾脏在从事高代谢需求活动的个体中起着关键作用。这可能也适用于人类，因为先前的研究表明，与生活在海平面附近的人相比，一些高海拔人群的脾脏更大，脾脏功能也显著增强。目前的项目将测量高海拔和低海拔生活人群在运动期间的脾脏功能，在这段时间内，两组人都在越来越高的海拔进行运动。该项目与一个为研究生和本科生提供研究机会的海外学习课程相关联，该研究还直接吸引了当地社区成员和实施伙伴。高原上的土著居民几千年来一直暴露在低气压的缺氧环境中。在一些这样的人群中，自然选择作用于与低循环血红蛋白浓度相关的基因[Hb]。在耐缺氧物种中，如潜水哺乳动物，在高代谢需求时，循环[Hb]是通过脾脏收缩来提高循环红细胞（rbc）的动态调节的。运动和缺氧暴露的人也会发生脾收缩。研究人员已经证明，一些适应高海拔的种群的静息脾脏体积比对照组大19-35%，脾收缩比对照组大5倍。这与在憋气潜水的海洋狩猎采集人群中记录的脾脏体积大35%相似；对屏气潜水人群的基因组分析表明，脾脏体积和/或人类潜水反应是积极的选择。本研究测试了自然选择改变了脾脏大小和脾脏收缩以优化高原有氧运动的假设，在从1440米到4370米的7天上升过程中，将评估脾脏体积、脾脏收缩、[Hb]变化和这段时间内血液动力学系统的其他特征。全基因组序列数据将用于探索在先验的兴趣位点和整个基因组的选择广泛。该方法将对脾和血液学表型与先前确定的候选基因以及通过用于确定定向选择基因组特征的群体遗传统计测试确定的最佳选择提名基因进行关联分析。积极的研究结果可能具有变革性，并将为未来世界各地高地土著人口适应性反应的生理和基因组工作开辟道路。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Some humans living in mountainous regions of the world are adapted to the low oxygen conditions of high-altitude, particularly notable during mountaineering activity. The main goal of this project is to examine the role of the human spleen in exercise tolerance at altitude, and to assess the ways in which this pressure has shaped the function of the spleen in populations who have lived and exercised at altitude for thousands of years. The spleen regulates circulating red blood cells and thus the oxygen carrying capacity of the blood; in other species (e.g., diving mammals, racehorses) research has shown that the spleen plays a critical role in individuals engaging in activity with high metabolic demand when oxygen is a limiting factor. This could also be true for humans, as prior work has documented larger spleens and significantly enhanced spleen function in some high-altitude populations compared to those living closer to sea level. The current project will measure spleen function during exercise in high- and low-altitude living populations over a length of time in which both groups are exercising at increasingly high altitudes. This project is linked to a study-abroad course which offers research opportunities for both graduate and undergraduate students, and the research also directly engages local community members and implementing partners. Highland native populations have been exposed to hypobaric hypoxia for millennia. In some such populations, natural selection has acted on genes which are associated with lower circulating hemoglobin concentration [Hb]. In hypoxia tolerant species like diving mammals, circulating [Hb] is dynamically regulated by contraction of the spleen to elevate circulating red blood cells (RBCs) during high metabolic demand. Splenic contraction also occurs in humans with exercise and hypoxia exposure. The researchers have documented that some high-altitude adapted populations have 19-35% larger resting spleen volume and 5-fold greater splenic contraction compared to controls. This is similar to the 35% larger spleen volume documented in breath-hold diving marine hunter-gatherer populations; genomic analysis of breath-hold diving populations suggest positive selection on spleen volume and/or the human diving response. This study tests the hypothesis that natural selection has modified spleen size and splenic contraction to optimize aerobic performance at altitude in the context of an incremental 7-day ascent to altitude from 1,440 to 4,370 meters where spleen volume, splenic contraction, changes in [Hb], and other features of the hemodynamic system during this time period will be assessed. Whole genome sequence data will be used to explore selection at loci of a priori interest and across the genome broadly. The approach will be to conduct association analyses of splenic and hematological phenotypes with previously identified candidate genes as well as the top selection-nominated genes identified via population genetic statistical tests used to identify genomic signatures of directional selection. Positive research findings could be transformative and would open avenues for future physiological and genomic work on the adaptive response of highland native populations around the world.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.