AltitudeOmics

The goal of this proposal is to advance high-altitude medical research by discovering the basic molecular
mechanisms of acclimatization that protect soldiers from high-altitude illness.

Acclimatization is the process by which people adjust to high altitudes, where oxygen in the air is quite low. If
an individual were to travel immediately from sea level to high-altitude, they would likely feel dizzy, be unable
to move rapidly, mentally sluggish, and might rapidly become ill with a headache and nausea. Thus, mountain
climbers and soldiers who plan to spend time at high altitude usually try to adjust slowly, often spending time at
moderate altitudes, then slowly climbing to higher altitudes. This allows their bodies to get used to breathing in
the thin air, and acclimatize. But soldiers often do not have a choice about how fast they have to go to high
altitude, and thus can be in harm’s way for developing high-altitude illness.
After we acclimatize, we are protected from high-altitude illness, and we have better exercise and mental
performance at high altitude. And when we come down from high altitude after becoming acclimatized, we
maintain a high degree of protection from high-altitude illness, whether we stay at low altitude or return to high
altitude. We also maintain our exercise performance if we come down, then return to high altitude.
To advance our understanding of what causes high-altitude illness, and what can be done to prevent it, we want
to further study these biological changes that occur in people’s bodies when they acclimatize, and how and why
such changes remain after time spent at low altitude. If we don’t acclimatize, or go too rapidly to high altitudes,
we can develop high-altitude illness. High-altitude illnesses challenge the soldier and civilian. For example, the
military often must send soldiers to high-altitude regions with short notice; as a result, these soldiers have very
little time to adjust to the low-oxygen environment. The three most common high-altitude illnesses are acute
mountain sickness (AMS), high altitude pulmonary edema and high altitude cerebral edema. The main
symptoms of AMS include headache, nausea, loss of appetite, difficulty sleeping, fatigue, and dizziness.
Currently, we know very little about the fundamental molecular mechanisms of high-altitude illness; i.e., what
happens deep within people’s bodies, even at the gene level, that makes people either acclimatize, or fail to and
become sick. The military is concerned about this issue, because soldiers need to be physically and mentally
ready to perform immediately upon arrival to high altitudes. Recently, we showed that when people spent 10
hours at high-altitude and low oxygen, a number of genes were “turned on”, and after 32 days of low oxygen in
mice, more than 500 genes are ‘turned on or off”. We think that this information about genes may help us
understand how to counter the challenge for humans who have to live with low oxygen in high-altitude
environments. If we don’t conduct research to better understand what happens to people’s bodies during
acclimatization, and how and why such changes persist when people return to low altitude, we will continue to
experience a major road-block to progress in high-altitude medicine and physiology. Our proposed study will
advance the field of high-altitude medicine and physiology by exploring, for the first time, the basic molecular
and cellular mechanisms of human responses to high altitude, and the persistence of these signaling systems on
return to low altitude as a new approach to solving the challenge posed to soldiers by high-altitude illnesses.
Interim outcomes that may lead to new clinical management strategies for preventing and treating high-altitude
illnesses include: 1) potential discovery of new biological pathways important for the onset and persistence of
acclimatization that are susceptible to manipulation by already approved drugs could result in new clinical trials
within months of completing our study; 2) using the same newly discovered pathways, new drugs could be
developed, or new drugs such as the prolyl hydroxlase enzymes which modulate oxygen sensing pathways,
could be used in clinical trials within months to years of completing this study; 3) matching the human
molecular response pathways that cause acclimatization and its persistence on descent to animals that have a
similar response could lead to development of animal models for the high-altitude illnesses (none currently
exist).
In summary, we propose to determine the molecular mechanisms underlying protection from high-altitude
illness conferred by acclimatization, and the persistence of this protection on return to low altitude. We believe
that these studies will rapidly advance the field of high-altitude medicine and biology, with ultimate benefit to
soldiers deployed to high-altitude regions of the world.