ROLE OF SULFATION IN THE PATHOLOGY OF CYSTIC FIBROSIS

硫酸化在囊性纤维化病理学中的作用

• 批准号: 3233202
• 负责人: ELIAS MEEZAN
• 金额: $ 14.45万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-12-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3233202
• 关键词: acidity /alkalinity; anions; cellular pathology; chlorine; cyclic AMP; cystic fibrosis; diffusion; erythrocyte membrane; fibroblasts; gel electrophoresis; glycoproteins; human subject; human tissue; inborn biological transport disorder; ion transport; laboratory rabbit; membrane channels; membrane potentials; molecular pathology; mucopolysaccharides; mucus; proteoglycan; secretion; stilbenes; sulfates; sulfation; sulfotransferase; sweat; tissue /cell culture; transport proteins

Cystic fibrosis is an inherited disorder, whose principal pathologic characteristic is the elaboration of viscous mucous secretions from many of the exocrine cells of the body. Studies of the composition of mucous glycoproteins and proteoglycans from tracheobronchial secretions of cystic fibrosis patients have shown these to exhibit increased sulfation of the carbohydrate chains, but the metabolic basis for this production of altered mucous components is unknown. Since cystic fibrosis appears to be a primary disorder of membrane ion transport characterized by increased sodium and chloride concentrations in sweat, altered S042- levels in tissue may be a primary or secondary consequence of the electrolyte abnormalities of this disease. Little attention has been paid to the possible role of S042- levels in this disease which may be a critical controlling factor in the production of abnormal sulfated glycoproteins. We have recently established that human lung and skin fibroblasts have carrier-mediated, SITS and DIDS-sensitive anion exchange transport systems for sulfate which are stimulated by protons and mediate H+SO4= cotransport. In these respects sulfate transport in these cells is strikingly similar to that mediated by the band 3 anion exchanger in erythrocytes. The sulfate uptake system in CF fibroblasts has an increased capacity compared to that of normals at both pH 7.5 and pH 5.5 and this alteration in transport function may lead to increased levels of intracellular sulfate and the production of oversulfated macromolecules. Moreover, if the CF fibroblast anion exchanger is a better sulfate and poorer chloride transporter than that of normals, it may reflect the generalized impermeability of membranes to chloride ion in this disease and suggest that there may be some structural and/or regulatory components which are common to the electroneutral anion exchanger and the conductive chloride channel, which appears to be the primary site of the defect in CF. Therefore, it is proposed to study the properties of the transport system of S042- , the activation of S042- to the sulfate donor PAPS and the effects of varying S042- levels, and agents which affect sulfate transport and sulfation, on the production of sulfated macromolecules in cultured IMR-90 human lung fibroblasts and in skin fibroblasts cultured from cystic fibrosis patients and age/sex-matched controls with no family history of the disease. The long term goal of this project is to better understand the ionic environment which leads to a change in the sulfation pattern of macromolecules in CF.

囊性纤维化是一种遗传性疾病，其主要 病理特征是粘液粘稠化 身体许多外分泌细胞的分泌物。 研究 粘液糖蛋白和蛋白聚糖的组成 囊性纤维化患者的气管支气管分泌物显示， 这些化合物表现出碳水化合物链的硫酸化增加， 但这种粘液产生的代谢基础 成分不明。 由于囊性纤维化似乎是一种 膜离子转运的原发性紊乱，特征为 汗液中的钠和氯浓度增加， 组织中的S 042水平可能是主要或次要后果 这种疾病的电解质异常。 很少注意 已支付的S 042-水平在这种疾病中的可能作用 这可能是生产中的关键控制因素， 异常硫酸化糖蛋白。 我们最近确定， 人肺和皮肤成纤维细胞具有载体介导、SITS和 硫酸盐的DIDS敏感阴离子交换运输系统， 受质子刺激并介导H+ SO 4 =共转运。 在这些 在这些细胞中的硫酸盐转运方面， 通过红细胞带3阴离子交换剂介导。的 CF成纤维细胞中的硫酸盐摄取系统具有增加的能力 与pH 7.5和pH 5.5的正常人相比， 运输功能的改变可能导致 细胞内硫酸盐和过硫酸盐的产生 大分子 此外，如果CF成纤维细胞阴离子交换剂是 一个更好的硫酸盐和更差的氯离子转运体比， 正常，它可能反映了膜的广义不透性 与氯离子有关，并表明可能有一些 共同的结构和/或调节组件， 电中性阴离子交换剂和导电氯离子通道， 这似乎是CF中缺损的主要部位。 因此，建议研究输运的性质 S 042-体系中，S 042-对硫酸盐供体PAPS的活化 以及不同S 042水平的影响，以及影响 硫酸盐运输和硫酸化，对硫酸盐的生产 在培养的IMR-90人肺成纤维细胞中和在 从囊性纤维化患者培养的皮肤成纤维细胞， 年龄/性别匹配的对照组，无家族病史。 本项目的长期目标是更好地了解 导致硫酸化模式变化的离子环境 CF中的大分子。