REGULATION OF C1 INHIBITOR SYNTHESIS

点击翻译按钮获取中文摘要

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.