ENDOTHELIAL CELL HYPOXIA ASSOCIATED PROTEINS

描述(根据申请者的抽象和具体目标改编)：这是 1993年1月资助的一项赠款的竞争性续期申请 描述一组特定和独特的内皮细胞(EC)应激 蛋白质在急性和/或慢性缺氧时上调。首字母 该项目的理论是，这些被称为缺氧相关蛋白的蛋白质 (HAPS)，可能有助于EC保持非凡的能力 在各种缺氧条件下细胞和功能的完整性 建议对这些HAP进行表征的研究。在这一资助期内， 调查人员对其中两个HAP进行了测序和鉴定，确定了它们的 内皮和应激的特异性，探索它们可能的功能， 研究了它们的调节并确定了它们在体外的存在 在活体内。为了进一步描述HAP的特征，请探索它们在 更多与生物相关的系统，并开发细胞和动物模型 一种确定其功能和意义、具体目标的手段 将：1)确定剩余的HAP；2)通过以下方式调查对HAP的监管 确定基因调控的部位，顺式作用的调控元件和 负责基因表达改变的反式作用因素；3)检查 联合应用改变HAPS表达对体外低氧反应的影响 转基因技术和反义寡核苷酸增加或 在含有HAPS的细胞中减少HAPS的表达，并表达HAPS 在通常不包含它们的细胞中；以及4)检查产物 以及HAPS在正常小鼠体内缺氧和发育过程中的作用 转基因动物。

DESCRIPTION (Adapted from applicant's abstract 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.