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.

Project Report

The goal of the study was to find out more about the ways that Tibetans living at high altitudes deliver the continuous supply of oxygen required for metabolism in their cells. Tibetans and others at high altitudes breathe air with relatively few oxygen molecules (called hypoxia) compared with low altitude. Unlike highlanders in South America who respond with substantially increased oxygen carrying capacity in their blood, Tibetans have relatively low oxygen carrying capacity in their blood. Yet Tibetans enjoy healthy, vigorous lives – thus suggesting the possibility of an alternative response to high-altitude hypoxia. The study asked whether Tibetans’ tiniest blood vessels, called capillaries, have a structure that changes blood flow and supplies enough oxygen for cells to function normally. It also asked whether similar structural responses occur in visitors to high altitude. A sample of Sherpas, a group of Tibetan descent living at 3800m (~12,500’) near Mt. Everest in Nepal, and one of Nepalis, a group of lowlanders working there temporarily participated in the study. A sample of lowlanders at low altitude provided a baseline. Both Sherpa and Nepalis had capillaries with fewer twists than the baseline, although they achieved that result differently. The Sherpa had more capillaries that were shorter and had fewer twists than the Nepalis and lowlanders. One reason may be the Sherpas’ higher average blood concentration of a protein that starts the growth of blood vessels. The Nepalis had longer capillaries than the other two groups with the result that they had the same relatively low number of twists as the Sherpa. At high altitude where oxygen in the air and the body is limited compared with low altitude, capillaries with fewer twists, however achieved, may enable more effective diffusion of available oxygen across a larger area and to more metabolizing cells. One of the broader impacts of this study is a better understanding that healthy people have more than one response to the physiological stress environmental hypoxia. Two-thirds of the deaths in the U.S. each year are associated with the hypoxia of disease yet there is little understanding of why some people respond successfully to a particular therapy and others do not. The result of this study suggests that individuals may respond differently to the hypoxia of disease and consequently could benefit from interventions tailored to their responses. Other broader impacts of this study include the involvement of the participants, research assistants, students and scientists in international research and the engagement of citizens of one country with those of another. The people who participated in and worked on the study learned about the research process, high-altitude human biology, and gained an appreciation of people and perspectives in the U.S. and Nepal.

Agency
National Science Foundation (NSF)
Institute
Division of Behavioral and Cognitive Sciences (BCS)
Type
Standard Grant (Standard)
Application #
0924726
Program Officer
Carolyn Ehardt
Project Start
Project End
Budget Start
2009-09-15
Budget End
2013-08-31
Support Year
Fiscal Year
2009
Total Cost
$319,403
Indirect Cost
Name
Case Western Reserve University
Department
Type
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44106