THE C1 INHIBITOR GENE AND HEREDITARY ANGIONEUROTIC EDEMA

对C1抑制物(C1INH)的功能和调节的专门知识 其基因可改善遗传性血管神经性水肿的治疗 (Hane)和C1INH可能发挥作用的其他条件。建议数 研究也将有助于我们对遗传病和 干扰素、白介素6和雄激素介导的基因突变 丝氨酸的调节和利用的抑制机制 蛋白水解酶抑制物(丝氨酸)家族。第一个具体目标是 继续对导致C1INH的突变的分子定义 虚弱和功能障碍。这些研究将检验这一假设 C1INH基因包含至少两个倾向增强的区域 朝向突变。第二个具体目标是针对分析 C1INH的结构与功能关系。这将是 主要通过对重组突变体C1INH的分析完成 分子。将要引入的突变将基于自然- 发生功能失调的突变，或基于分子预测 模特儿。这一具体目标将涉及三个问题：决定因素 靶标蛋白酶的特异性，采取的结构重排 在复合体形成过程中放置在抑制剂中，并发挥其功能作用 蛋白的高度糖基化的氨基末端结构域。这个 第三个特定目的是探索C1INH的表达调控 吉恩。我们假设C1INH基因的精确调控 多个诱导剂协同作用的结果， 包括γ-干扰素、白介素6和雄激素。引发剂驱动的启动子 基因的特征，以及顺式作用元件， 影响其功能。已知的C1INH表达的主要调节因子 是γ-干扰素和IL-6。对相关元素的描述 将完成对这些试剂的诱导，以及表征 雄激素的影响。最后，将检查鼠标是否具有 适合用于开发Hane的模型。初步数据 暗示它的效用。如果支持此功能，则C1INH缺陷鼠标将 将使用基因敲除技术进行开发。这将允许精确地 疾病和体内症状的介体的特征 基因调控分析。这将是最终的必然 促进C1INH在本病中表达的药物分析 这种缺陷的杂合子个体会出现症状 州政府。

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.