Role of MU5AC Mucins in Airway Disease

MU5AC 粘蛋白在气道疾病中的作用

• 批准号: 6987848
• 负责人: Mary C Rose
• 金额: $ 36.03万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-03-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6987848
• 关键词: clinical research

DESCRIPTION (provided by applicant): Airway mucus obstruction, a major cause of morbidity and mortality in cystic fibrosis (CF) patients, is largely attributed to overproduction and hypersecretion of mucin glycoproteins (mucins). Sustained mucin hypersecretion requires increased expression of mucin (MUC) genes that encode the protein backbone of mucins. Recent reports have indicated that CF airways have an intrinsically high inflammatory milieu, prior to bacterial infection, that promotes mucin overproduction. We have recently shown that IL8 increases in vitro expression of two airway mucin genes, MUC5AC and MUC5B, by increasing mucin mRNA stability. Importantly, elevated levels of IL8 in the airways of CF patients prior to and after infection suggest that IL8 can initiate and maintain increased mucin gene expression in vivo. Glucocorticoids decrease airway inflammation and mucin production in vivo by multi-factorial mechanisms, including alterations in expression of anti-inflammatory proteins or cytokines. GC also decreases mucin gene expression in vitro. A better understanding of mucin gene regulation by pro-and anti-inflammatory mediators, as well as the ontogeny of inflammatory mediators in CF lungs, should ultimately result in therapies that circumvent increased mucin gene expression and mucus obstruction in CF airways. Three aims are proposed to address this objective. In Aim 1, the hypothesis that IL8 increases mucin mRNA stability in airway epithelial cells by altering expression of RNA-binding proteins (RBP) that recognize specific cis-sequences in the 3' untranslated region of mucin genes or by mediating expressions of genes that regulate or encode RBP will be tested by EMSA, mutation analysis, transfection assays and gene expression analyses. In Aim 2, the hypothesis that GC decrease MUC5AC gene expression in airway epithelial cells by down-regulating transcriptions factors that interact at or near GC response elements in the 5'-upstream flanking sequences of MUC5AC and/or by altering expression of anti-or pro-inflammatory genes that mediate mucin gene expression will be investigated. In Aim 3, candidate genes involved in airway mucin overproduction will be identified and assessed by gene expression array profiling of respiratory tract tissues from CF and non-CF patients to test the hypothesis that airway mucus obstruction in CF patients is a consequence of the defective CF gene, which results in altered expression of genes that mediate airway homeostasis, including mucin production.

描述（由申请人提供）：气道粘液阻塞是囊性纤维化（CF）患者发病率和死亡率的主要原因，主要归因于粘蛋白糖蛋白（粘蛋白）的过量生产和过度分泌。持续性粘蛋白过度分泌需要增加编码粘蛋白蛋白主链的粘蛋白（MUC）基因的表达。最近的报道表明，在细菌感染之前，CF气道具有本质上较高的炎症环境，从而促进粘蛋白过量产生。我们最近表明，IL8通过增加粘蛋白mRNA稳定性来增加两个气道粘蛋白基因MUC5AC和MUC5B的体外表达。重要的是，感染前后CF患者气道中的IL8水平升高表明IL8可以启动并维持体内粘蛋白基因表达增加。糖皮质激素可通过多因素机制在体内减少气道炎症和粘蛋白产生，包括改变抗炎蛋白或细胞因子的表达。 GC还降低了体外粘蛋白基因表达。更好地了解CF肺中抗炎和抗炎介质的粘蛋白基因调节，以及炎症介质的个体发育，最终应导致疗法，以避免CF气道中粘蛋白基因表达和粘液阻塞的增加。提出了三个目标来解决这一目标。在目标1中，假设IL8通过改变RNA结合蛋白（RBP）的表达来增加粘蛋白上皮细胞中的粘蛋白mRNA稳定性，这些蛋白（RBP）识别粘蛋白基因的3'未翻译区域中特定的顺式序列或通过介导了调节或包含rbp的基因表达的表达或分析的基因表达来分析emsa andsa sysa，transa，noffection contection andsa consagation constage andsa，contraniz contfunf intrane contrane constage sance sance。在AIM 2中，假设GC通过下调的转录因子降低了气道上皮细胞中MUC5AC基因的表达，这些因子在MUC5AC和/或通过介导Mucucin Gene表达的抗炎性基因表达的5'上游侧翼序列中相互作用或接近GC响应元件相互作用。在AIM 3中，将通过基因表达阵列分析CF和非CF患者的呼吸道组织的基因表达阵列分析来测试CF患者的气道粘液阻塞是CF基因的结果，这导致基因介导空气毒素的表达改变了MUCUCCIN，CF患者的结果是，CF患者的呼吸道组织的结果是，CF患者的呼吸道组织的变化，包括MECTAIRS的介导，将鉴定出媒体表达阵列的基因表达阵列分析，从而确定和评估了基因介导促进空气毒素的表达。