PROJECT SUMMARY Hypoxia is a condition in which the body is deprived of an adequate supply of oxygen which can lead to severe damage to various tissues and organs and can have serious implications for the health and well-being of the affected individual. Exposure to high altitudes is a common cause of hypoxia; populations who permanently reside at high altitudes are exposed to chronic hypoxia, while populations only visiting high altitudes for a short period are exposed to acute hypoxia. High-altitude human populations and certain animal models have been extensively utilized to examine physiological changes associated with rapid plastic responses to acute hypoxia and long-term adaptive response to chronic hypoxia. Recent genomic studies of high-altitude human populations have provided key insights into the genetic basis of long-term adaptation to hypoxia. E.g., genetic variations in the genes associated with hypoxia-inducible factors (HIFs) pathways are known to play a critical role in the chronic hypoxia response. While the genetic basis of long- term adaptation to hypoxia is well studied, we still have a limited understanding of the underlying genomic regulation associated with plastic response to acute hypoxia. In addition, little is known about how the duration and frequency of hypoxia exposure may play a role in such plastic and adaptive responses. Thus, the working hypothesis of this proposal is that the plastic and adaptive response to hypoxia may vary according to the amount of time an individual spends under hypoxic conditions. To test this hypothesis, we will study birds residing across the elevational gradient in the Himalayas and Tibetan plateau that demonstrate natural acclimation/adaptation to acute/chronic hypoxia. We propose two specific aims: the first aim will quantify intra- and inter-species changes in hematological traits associated with chronic hypoxia and study the genomics/transcriptomics profiles in low/high altitude residents and altitudinal migrants to identify the underlying genetic basis of physiological traits associated with long-term adaptation to hypoxia. The second aim will expose birds to their “non-native” elevation via transplantation experiments and measure plasticity in hematological traits and gene expression profiles to identify gene regulatory mechanisms associated with rapid acclimation to acute hypoxia. The proposed research is scientifically important because understanding the genetic basis of acute and chronic hypoxia responses has implications for human health. The data generated from the proposed study will provide critical insights into the genetic factors associated with short and long-term hypoxia exposure that can be used to infer risk factors of multiple diseases associated with hypoxia and identify potential targets for drug development.