THE C1 INHIBITOR GENE AND HEREDITARY ANGIONEUROTIC EDEMA

C1抑制剂（C1 INH）功能和调节的具体知识 其基因可导致遗传性血管神经性水肿的改进治疗 （HANE）和C1 INH可能发挥作用的其他条件。 拟议 研究也将有助于我们了解遗传疾病， 干扰素、白细胞介素-6和雄激素介导基因的诱变 调节和抑制机制的丝氨酸 蛋白酶抑制剂（丝氨酸蛋白酶抑制剂）家族。 第一个具体目标将 继续导致C1 INH突变的分子定义 缺陷和功能障碍。 这些研究将检验以下假设： C1 INH基因包含至少两个具有增强的倾向性的区域， 走向突变 第二个具体目标是分析 C1 INH的结构功能关系。 这将是 主要通过分析重组突变体C1 INH 分子。 将引入的突变将基于自然- 发生功能失调的突变体，或者根据分子生物学的预测， 建模 这一具体目标将涉及三个问题： 靶蛋白酶特异性的结构重排， 在复合物形成过程中， 蛋白质的氨基末端结构域。 的 第三个具体的目的是探讨C1 INH的表达调控 基因 我们假设C1 INH基因的精确调控 是多种诱导剂协同作用的结果， 包括γ-IFN、IL-6和雄激素。 引发剂驱动的启动子 基因的特性，以及顺式作用元件， 影响其功能。 C1 INH表达的主要已知调节因子 是γ-干扰素和IL-6。 对责任因素的定性 将完成这些药物的诱导，以及表征 雄激素的作用 最后，将检查小鼠的 适用于开发HANE模型。 初步数据 表明其效用。 如果这一点得到支持，C1 INH缺陷小鼠将 使用基因敲除技术开发。 这将允许精确的 疾病和体内症状介质的表征 基因调控分析。 这将是一个必要的最终 分析增强该疾病中C1 INH表达的试剂，其中 症状出现在对于缺陷为杂合子的个体中 状态

Specific knowledge of C1 inhibitor (C1INH) function and of regulation of its gene can lead to improved therapy of hereditary angioneurotic edema (HANE) and other conditions in which C1INH may play a role. The proposed studies also will contribute to our understanding of genetic disease and mutagenesis, of interferon, interleukin-6 and androgen-mediated gene regulation and of the inhibitory mechanism utilized by the serine proteinase inhibitor (serpin) family. The first specific aim will continue the molecular definition of mutations that result in C1INH deficiency and dysfunction. These studies will test the hypothesis that the C1INH gene contains at least two regions with an enhanced propensity toward mutation. The second specific aim is directed toward an analysis of the structure function relationships in C1INH. This will be accomplished primarily via analysis of recombinant mutant C1INH molecules. Mutations to be introduced will be based either on naturally- occurring dysfunctional mutants, or on predictions made from molecular modeling. This specific aim will approach three issues: the determinants of target protease specificity, the structural rearrangements that take place in the inhibitor during complex formation, and the functional role of the heavily glycosylated amino terminal domain of the protein. The third specific aim will explore the regulation of expression of the C1INH gene. We hypothesize that the precise regulation of the C1INH gene results from the cooperative interaction of multiple inducing agents, including gamma-IFN, IL-6 and androgens. The initiator driven promoter of the gene will be characterized, as will the cis-acting elements that influence its function. The major known regulators of C1INH expression are gamma-IFN and IL-6. The characterization of the elements responsible for induction of these agents will be completed, as will characterization of the effects of androgens. Finally, the mouse will be examined for its suitability to use for development of a model of HANE. Preliminary data suggest its utility. If this is supported, a C1INH deficient mouse will be developed using gene knockout technology. This would allow precise characterization of the mediators of symptoms in the disease and in vivo analysis of gene regulation. This would be a necessity for the ultimate analysis of agents to enhance C1INH expression in this disease in which symptoms develop in individuals who are heterozygous for the deficiency state.