and specific aims): This is a competitive renewal application of a grant funded in January 1993 to characterize a specific and unique set of endothelial cell (EC) stress proteins upregulated during acute and/or chronic hypoxia. The initial project theorized that these proteins, termed hypoxia associated proteins (HAPs), might contribute to the remarkable ability of EC to maintain cellular and functional integrity during various hypoxic conditions and proposed studies to characterize these HAPs. In this funding period, the investigators sequenced and identified two of the HAPs, determined their endothelial and stress specificity, explored their possible functions, investigated their regulation and determined their existence both ex vivo and in vivo. To characterize the HAPs further, explore their existence in more biologically relevant systems and develop cellular and animal models as a means to determine their function and significance, the specific aims will: 1) Identify the remaining HAPs; 2) Investigate regulation of HAPs by defining the site of gene regulation, the cis-acting regulatory elements and trans-acting factors responsible for altered gene expression; 3) Examine the effect of altering HAPs expression on the response to hypoxia in vitro using transfection techniques and antisense oligonucleotide to increase or decrease HAPs expression in cells that do contain them and to express HAPs in cells that do not normally contain them; and 4) Examine the production and role of HAPs in vivo in normal mice during hypoxia and by development of transgenic animals.
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