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地区的低氧条件，尤其是在登山活动期间。该项目的主要目标是研究人类脾在高原运动耐力中的作用，并评估这种压力是如何影响数千年来在高原生活和锻炼的人群的脾功能的。脾调节循环中的红细胞，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，当氧气是限制因素时，脾在从事高代谢需求活动的个人中起着关键作用。这也可能适用于人类，因为之前的研究已经证明，与那些生活在海平面附近的人相比，一些高海拔地区的人脾更大，脾功能显著增强。目前的项目将测量生活在高海拔和低海拔地区的人群在锻炼期间的脾功能，这两组人都在越来越高的海拔地区锻炼。该项目与一个为研究生和本科生提供研究机会的出国留学课程相联系，该研究还与当地社区成员和执行伙伴直接接触。数千年来，高地原住民一直处于低压低氧环境中。在一些这样的人群中，自然选择作用于与循环中较低的血红蛋白浓度[Hb]相关的基因。在耐缺氧的物种中，如潜水哺乳动物，循环[Hb]受到脾收缩的动态调节，以在高代谢需求时提高循环中的红细胞(RBC)。在运动和低氧暴露的人类中，也会发生脾收缩。研究人员已经证明，与对照组相比，一些高海拔适应人群的静息脾体积增加了19%-35%，脾收缩增加了5倍。这与屏气潜水海洋狩猎采集人群中记录的大35%的脾体积相似；对屏气潜水人群的基因组分析表明，对脾体积和/或人类潜水反应的选择是积极的。这项研究测试了这样一种假设，即自然选择已经改变了脾的大小和脾的收缩，以优化在海拔从1,440米到4,370米的7天递增攀升中的有氧表现，在此期间将评估脾体积、脾收缩、[Hb]的变化和血液动力学系统的其他特征。全基因组序列数据将被用来探索先验感兴趣的基因座和广泛的基因组范围内的选择。该方法将进行脾和血液学表型与先前确定的候选基因以及通过用于识别定向选择的基因组特征的群体遗传统计测试确定的顶级选择提名基因的关联分析。积极的研究成果可能具有变革性，并将为未来在世界各地高原原住民适应反应方面的生理和基因组工作开辟道路。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.