REGULATION OF C1 INHIBITOR SYNTHESIS

描述：C1抑制剂(C1INH)是一种丝氨酸蛋白酶抑制剂， 调节经典补体途径和接触的激活 激肽生成系统。C1INH的正常调节似乎取决于 对干扰素(干扰素)、IL-6和可能的 皮质类固醇和雄激素。调查员提议 用TATA非引发剂驱动的C1INH启动子进行表征 报告基因构建、电泳率漂移和DNA酶I 使用定点突变的足迹分析来定义 必需的元素。干扰素刺激反应的特性 第一内含子和上游INF-Gamma中的元素(ISRE) 将完成激活序列(GAS)及其相关角色 在干扰素-α和干扰素-γ对C1INH的调节中，将对其进行定义。这个 雄激素/糖皮质激素与IL-6反应的功能 元素将被定义，假设的相互作用也将被定义 核因子IL-6与雄激素/糖皮质激素受体一 突变体C1INH已被描述为似乎抑制了 正常的野生型文字记录。这种抑制的机制将 要下定决心。这一观察结果可能对 杂合子发生的其他疾病的合成调节 缺乏状态和合成的正常调节。

DESCRIPTION: C1 inhibitor (C1INH) is a serine proteinase inhibitor that regulates activation of the classical complement pathway and the contact system of kinin generation. Normal regulation of C1INH appears to depend upon responsiveness to interferons (IFN), IL-6 and possibly to corticosterioids and androgens. The investigator proposes to characterize the TATA-less initiator driven C1INH promoter using reporter constructs, electrophoretic mobility shift and DNase I footprinting assays with site directed mutagenesis to define the required elements. The characterization of the IFN-stimulated response elements (ISRE) in the first intron and the upstream INF-gamma activation sequences (GAS) will be completed, and their relative roles in regulation of C1INH by IFN-alpha and IFN-gamma will be defined. The function of the putative androgen/ glucocorticoid and IL-6 responsive elements will be defined, as will the hypothesized interaction between nuclear factor IL-6 and the androgen/ glucocorticoid receptors. One mutant C1INH has been described that appears to inhibit translation of the normal wild type transcript. The mechanism of this inhibition will be determined. This observation may have important implications for regulation of synthesis in other diseases that develop in heterozygous deficiency states and for normal regulation of synthesis.