REGULATION OF C1 INHIBITOR SYNTHESIS

C1 抑制剂合成的调控

• 批准号: 6128977
• 负责人: ALVIN E DAVIS
• 金额: $ 14.58万
• 依托单位: IMMUNE DISEASE INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6128977
• 关键词: DNA footprinting; androgens; biosynthesis; complement inhibitors; gel mobility shift assay; genetic promoter element; genetic regulation; glucocorticoids; interferons; interleukin 6; nucleic acid sequence; reporter genes; site directed mutagenesis; steroid hormone receptor

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.

描述：C1抑制剂（C1 INH）是一种丝氨酸蛋白酶抑制剂， 调节经典补体途径的激活， 激肽生成系统。C1 INH的正常调节似乎取决于 在对干扰素（IFN）、IL-6和可能的 皮质类固醇和雄激素。研究者建议 表征TATA-少引发剂驱动的C1 INH启动子，使用 报告基因构建体、电泳迁移率漂移和DNA酶I 使用定点诱变的足迹分析来确定 所需的元素。 IFN刺激反应的表征 第一内含子和上游INF-γ中的ISRE元件 激活序列（GAS）将完成，以及它们的相对作用 将定义IFN-α和IFN-γ对C1 INH的调节。的 假定的雄激素/糖皮质激素和IL-6反应性的功能 元素将被定义，因为将假设之间的相互作用， 核因子IL-6和雄激素/糖皮质激素受体。 一 已经描述了突变体C1 INH，其似乎抑制 正常的野生型转录本。 这种抑制的机制将 被确定。这一观察结果可能对以下方面具有重要意义： 在其他杂合性疾病中的合成调节 缺乏状态和合成的正常调节。