BIOCHEMISTRY OF CYSTIC FIBROSIS MUCOUS SECRETIONS

囊性纤维化是世界上最常见的致死性遗传病。 高加索人。在慢性阻塞性肺疾病中，呼吸道粘液有高分泌。 具有改变的物理性质，从而导致能力受损 疏通呼吸道，从而导致失去正常的保护功能 粘液分泌。这些因素在这些因素中发挥着重要作用。 慢性阻塞性肺疾病的呼吸窘迫和进行性肺损害。它是 普遍认为肺部受累是导致大多数 慢性阻塞性肺疾病患者的发病率和死亡率。最近，取得了重大进展 发生在定义CF的遗传学和表征基础上 各种上皮细胞中有关电解质和蛋白质的生化缺陷 流体运输。尽管取得了这些进展，但导致 粘液的过度分泌尚不完全清楚。我们假设 特异性粘蛋白基因在CF中的表达更高。自粘液 糖蛋白(粘蛋白)(由表面杯和粘膜下腺分泌 细胞)是粘液的主要大分子成分， 负责其粘弹性和凝胶形成特性、变化 粘液中的粘蛋白可能影响粘液的生理行为。有最少的 四个人粘蛋白基因在呼吸道上皮细胞中的表达 这些基因在CF和正常呼吸道上皮中的表达尚不清楚。 最近，我们实验室已经鉴定并鉴定了一个部分cdna。 它编码一种主要的呼吸道粘蛋白，似乎是组织特异性的(3)。 我们现在已经进一步表征了该cdna的羧基末端，并且已经 严格证明了该基因确实编码了一种主要的呼吸道粘蛋白。这个 Cdna代表了一种新的粘蛋白基因的一部分，暂定地，我们 已经命名为MUC8。CF和正常呼吸道组织均显示高水平的血管活性物质 MUC8的表达，它似乎是MUC8的主要粘蛋白信息之一 航空公司。我们研究的长期目标是阐明这一角色 呼吸道粘蛋白在健康和疾病中的作用。这项提案的总体目标是 也是为了表征新的主要呼吸道粘蛋白MUC8的基因 作为研究其调控和表达的工具。这样做的具体目的是 应用范围如下：1)鉴定和鉴定全长cDNA 编码人类主要呼吸道粘蛋白MUC8；2)确定相对分子 气道粘蛋白基因(MUC2、MUC4、MUC5和MUC8)在慢性阻塞性肺疾病中的表达 3)粘液中MUC8转录本的检测 用原位杂交法测定分泌细胞； MUC8基因的组织和鉴定 参与MUC8基因的表达和5)研究其影响 促分泌剂对MUC8基因表达的调节。这个 已建立的重组DNA技术的工具和程序以及 分子生物学将用于了解MUC8基因 呼吸道上皮细胞的组织、调节和表达。这个 从这些研究中获得的知识对于发展 治疗CF的合理方法最终将需要 控制粘液分泌速度及其粘度的能力。

Cystic fibrosis (CF) is the most common lethal genetic disease in Caucasians. In CF, there is a hypersecretion of the respiratory mucus with altered physical properties which results in an impaired ability to clear the airways and thus causing a loss of normal protective function of the mucus secretions. These factors play an important role in the respiratory distress and progressive pulmonary involvement in CF. It is generally agreed that pulmonary involvement is responsible for most of the morbidity and mortality in CF patients. Recently, major advances have occurred in defining the genetics of CF and characterizing the basis biochemical defect in various epithelia with regard to electrolyte and fluid transport. Despite these advances, the molecular events leading to hypersecretion of mucus are not fully understood. We hypothesize that specific mucin genes are more highly expressed in CF. Since mucin glycoproteins (mucins) (secreted by surface goblet and submucosal gland cells) are the major macromolecular components of the mucus and are responsible for its viscoelastic and gel forming properties, alterations in mucins may affect the physiological behavior of mucus. There are least four human mucin genes expressed in airway epithelium; the relative expression of these genes is not known in CF and normal airway epithelium. Recently, our laboratory has identified and characterized a partial cDNA that encodes a major airway mucin which appears to be tissue specific (3). We have now further characterized this cDNA at the carboxyl end and have rigorously proved that the cDNA truly encodes a major airway mucin. The cDNA represents a portion of a novel mucin gene, which, tentatively, we have named MUC8. Both CF and normal airway tissues showed high level of expression of MUC8 which appears to be one of the major mucin messages in the airways. The long-term goal of our research is to elucidate the role of airway mucins in health and disease. The overall goal of this proposal is to characterize the gene for the novel major airway mucin MUC8 as well as study its regulation and expression. The specific aims of this application are: 1) to identify and characterize the full length cDNA encoding the major human airway mucin MUC8; 2) to determine the relative expression of airway mucin genes (MUC2, MUC4, MUC5 and MUC8) in CF and normal tracheobronchial tissue; 3) to detect the MUC8 transcript in mucus secreting cells using in situ hybridization; 4) to determine the organization of the MUC8 gene and identify regulatory elements that are involved in the MUC8 gene expression and 5) to investigate the influence of secretagogues on the regulation of MUC8 gene expression. The established tools and procedures of recombinant DNA technology and molecular biology will be applied to the understanding of MUC8 gene organization, regulation and expression in the airway epithelium. The knowledge gained from these studies would be essential in order to develop a rational approach to the treatment of CF which will ultimately require an ability to control the rate of mucus secretion and its viscosity.