Regulation of pulmonary inflammation in cystic fibrosis by ceramide

神经酰胺对囊性纤维化肺部炎症的调节

• 批准号: 39194737
• 负责人: Professor Dr. Erich Gulbins
• 金额: --
• 依托单位: Institut für Molekularbiologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/39194737?language=en
• 关键词: Regulation; pulmonary; inflammation; cystic; fibrosis

Cystic fibrosis (CF), the most common autosomal recessive disorder in Western countries, is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) molecule and affects approximately 40 000 patients in Europe. The disease is characterized by chronic pulmonary inflammation, reduced mucociliary clearance, and increased susceptibility to infection. Our studies using Cftr-deficient mice and human CF specimens show that ceramide accumulates in the lungs and mediates increased cell death, susceptibility to infections, and inflammation. The molecular mechanisms of (aseptic) inflammation in cystic fibrosis lungs have not yet been defined. In the present study, we aim to determine whether ceramide mediates chronic inflammation in the lungs of Cftr-deficient mice through (i) activation of CD95, caspase 1 and the inflammasome, (ii) a dysfunction of tight junctions, (iii) an alteration of the expression and function of adhesion proteins in endothelial cells and (iv) a dysregulation of alvealor macrophages.

囊性纤维化（CF）是西方国家最常见的常染色体隐性遗传病，由囊性纤维化跨膜传导调节因子（CFTR）分子突变引起，在欧洲约有40000例患者。该疾病的特征在于慢性肺部炎症、粘膜纤毛清除减少和感染易感性增加。我们使用Cftr缺陷小鼠和人类CF标本的研究表明，神经酰胺在肺部积聚，并介导细胞死亡增加，对感染和炎症的易感性增加。囊性纤维化肺中（无菌）炎症的分子机制尚未确定。在本研究中，我们的目的是确定神经酰胺是否介导慢性炎症Cftr缺陷小鼠的肺部通过（i）激活CD95，半胱天冬酶1和炎症体，（ii）的紧密连接功能障碍，（iii）的表达和功能的改变粘附蛋白在内皮细胞和（iv）肺泡巨噬细胞的失调。