THE C1 INHIBITOR GENE AND HEREDITARY ANGIONEUROTIC EDEMA

C1 抑制剂基因与遗传性血管神经性水肿

• 批准号: 2198444
• 负责人: ALVIN E DAVIS
• 金额: $ 19.74万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2198444
• 关键词: androgens; chimeric proteins; complement inhibitors; disease /disorder model; gene expression; gene mutation; genetic enhancer element; genetic promoter element; hereditary angioneurotic edema; human genetic material tag; human tissue; interferon gamma; interleukin 6; laboratory mouse; nucleic acid sequence; polymerase chain reaction; protease inhibitor; protein structure function; site directed mutagenesis; tissue /cell culture; transfection

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.

C1抑制剂（C1INH）功能的特定知识和调节 它的基因可以改善遗传性血管尿素水肿的治疗 （Hane）和C1inh可能发挥作用的其他条件。 提议 研究还将有助于我们理解遗传疾病和 干扰素，白介素6和雄激素介导的基因的诱变 丝氨酸使用的调节和抑制机制 蛋白酶抑制剂（SERPIN）家族。 第一个特定目标将 继续对导致C1inh的突变的分子定义 缺陷和功能障碍。 这些研究将检验以下假设 C1INH基因至少包含两个区域，具有增强的倾向 走向突变。 第二个特定目标是针对分析的 C1INH中的结构函数关系。 这将是 主要通过分析重组突变体C1INH完成 分子。 要引入的突变将基于自然 - 发生功能失调的突变体或分子预测 造型。 这个具体目标将解决三个问题：决定因素 目标蛋白酶特异性的结构重排 在复杂形成过程中放置​​在抑制剂中，功能作用 蛋白质的重糖基化氨基末端结构域。 这 第三个特定目标将探索C1INH表达的调节 基因。 我们假设C1INH基因的精确调节 来自多种诱导剂的合作相互作用的结果， 包括γ-IFN，IL-6和雄激素。 发起者驱动器启动子 该基因将被表征，顺式作用元素也将 影响其功能。 C1inh表达的主要已知调节剂 是γ-IFN和IL-6。 负责元素的表征 为了诱导这些代理，将完成，表征 雄激素的作用。 最后，将检查鼠标的 适用于开发Hane模型的适用性。 初步数据 建议其效用。 如果支持这一点，C1INH缺乏的鼠标将 可以使用基因敲除技术开发。 这将允许精确 疾病和体内症状介体的表征 基因调控分析。 这将是最终的必要 分析药物以增强这种疾病中C1INH表达的分析 杂合的个人因缺乏症而出现症状 状态。