REGULATION OF C1 INHIBITOR SYNTHESIS AND CATABOLISM

维持正常的C1抑制剂（Clinh）血清水平取决于 Clinh合成与催化剂之间的平衡。 Clinh 有缺陷的病人代表了一种“自然实验”， 这种平衡就失去了。 遗传性血管性水肿（HAE）患者 同时具有异常的Clinh基因和获得性基因缺陷 表情 对于获得性Clinh缺乏症患者， 克林的加速消耗， 修饰的（94 kD）Clinh的无活性形式。 克林研究 这些患者的合成和分解代谢异常提供了 独特的机会来阐明克林机制 体内平衡 外周血单核细胞和肝癌细胞模型已经被 建立了体外研究Clinh分泌。 γ干扰素 刺激来自两种细胞类型的Clinh分泌。 的影响 达那唑（增加血清中Clinh水平）对Clinh分泌的影响 将被确定。 HAE患者的单核细胞将 在添加和不添加γ干扰素或达那唑的情况下培养。 将测量他们的Clinh分泌并与正常人进行比较 单核细胞 Clinh分泌率与以下因素相关： 通过定量测定表达的Clinh mRNA水平 北方印迹分析。 合成缺陷的性质 因此，这些药物的作用将局限于 翻译前或翻译后水平。 纯化蛋白中丝氨酸蛋白酶与Clinh的相互作用 将通过测量蛋白水解来分析系统和血浆中的蛋白质 活性、蛋白酶-Clinh复合物形成和94 kD Clinh 一代 通过研究这些参数， 蛋白酶在不同的摩尔比，生化机制， 将测定94 kD Clinh形成。 结构性 将评估94 kD Clinh和天然Clinh之间的关系 通过氨基酸末端基团分析。 放射性标记的94 kD Clinh将 用于计算94 kD的部分分解代谢率 AC 1D和其他患者的Clinh。 这些实验的结果应该会导致改善 治疗性增加血清和组织的策略 Clinh水平。 这将不仅有助于治疗 Clinh缺乏的患者，也要限制与古典 补体系统在其他炎症性疾病中的激活。

Maintenance of a normal C1 inhibitor (Clinh) serum level depends on the balance between Clinh synthesis and its catabolism. Clinh deficient patients represent one "experiment of nature" where this balance is lost. Patients with hereditary angioedema (HAE) have both an abnormal Clinh gene and an acquired defect in gene expression. In patients with acquired Clinh deficiency, there is accelerated consumption of Clinh with the generation of a modified (94 kD) inactive form of Clinh. The study of Clinh synthetic and catabolic abnormalities in these patients provides a unique opportunity to elucidate the mechanisms of Clinh homeostasis. Peripheral blood monocyte and hepatoma cell models have been established to study Clinh secretion in vitro. Gamma interferon stimulates Clinh secretion from both cell types. The effect of danazol (which increases serum levels of Clinh) on Clinh secretion will be determined. Monocytes from HAE patients will be cultured with and without added gamma interferon or danazol. Their Clinh secretion will be measured and compared to normal monocytes. The rates of Clinh secretion will be correlated with levels of expressed Clinh mRNA determined by quantitative Northern blotting analysis. The nature of the synthetic defect(s) in HAE and the action of these agents will thus be localized to either a pre-translational or post-translational level. The interactions of serine proteases with Clinh in purified protein systems and in plasma will be analyzed by measuring proteolytic activity, protease-Clinh complex formation, and 94 kD Clinh generation. By studying these parameters in the relevent proteases at various molar ratios, the biochemical mechanism of 94 kD Clinh formation will be determined. The structural relationship between 94 kD Clinh and native Clinh will be assessed by amino acid end group analysis. Radiolabeled 94 kD Clinh will be utilized to calculate the fractional catabolic rate of 94 kD Clinh in AC1D and other patients. The results of these experiments should lead to improved strategies for therapeutically increasing the serum and tissue Clinh levels. This will be useful not only in the treatment of Clinh deficient patients, but also to limit contact and classical complement system activation in other inflammatory diseases.