ENDOTHELIAL CELL HYPOXIA-ASSOCIATED PROTEINS

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In vivo, organisms and their resident tissues and cells are frequently exposed to decreases in ambient oxygen. Therefore, tolerance to acute hypoxia and, in some cases, adaptation to chronic hypoxia, is critical to survival and varies among different cells. Some of the adaptive strategies permitting development of hypoxia tolerance have been proposed and evaluated; others are likely unknown. We have recently identified a specific set of stress proteins induced in hypoxia tolerant endothelial cells during exposure to both acute and chronic hypoxia. These proteins, termed hypoxia associated proteins (HAPs), are specifically induced by environmental hypoxia, are distinct from other described stress proteins, such as heat shock or glucose-regulated proteins, and are likely regulated at the RNA level. To characterize endothelial cell HAPs and their regulation more fully, we will: 1) examine the localization of HAPs within pulmonary arterial endothelial cells; 2) investigate the relationship of HAPs and other stress proteins as protection against the toxic effects of hypoxia, heat shock, and glucose deprivation; 3) isolate HAPs by direct protein sequencing and by cloning HAPs cDNA from a hypoxia stimulated pulmonary arterial endothelial cell cDNA library; 4) use the isolated protein or the protein sequence deduced from HAPs cDNA to develop molecular probes; and 5) use antibody and cDNA probes to investigate transcriptional and translational regulation of HAPs in cultured cells and hypoxic tissues and to determine the effect of altering HAPs expression on endothelial cell response to hypoxia. These studies will provide insight into the regulation of HAPs at the biologic and genetic level and may provide markers for hypoxia in cells and tissues.