Reduced Generation of Multiple Motile Cilia: A severe novel respiratory ciliopathy

多运动纤毛生成减少：一种严重的新型呼吸纤毛病

• 批准号: 325271870
• 负责人: Professor Dr. Heymut Omran
• 金额: --
• 依托单位: Klinik für Kinder- und Jugendmedizin - Allgemeine Pädiatrie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/325271870?language=en
• 关键词: Reduced; Generation; Multiple; Motile; Cilia

Multiple motile cilia line our airways and make an essential contribution to clearing the upper and lower respiratory tract to prevent infection and chronic inflammatory. We have been able to describe a novel motile ciliopathy within the group of mucociliary clearance disorders: Reduced Generation of Multiple Motile Cilia (RGMC). RGMC affected suffer from chronic destructive airway disease. Unfortunatelly RGMC is difficult to diagnose because secondary changes caused by inflammation can resemble the picture seen in respiratory epithelia of RGMC affected. In RGMC there is markedly reduced formation of cilia and/or ciliated cells due to autosomal recessive mutations in CCNO and MCIDAS. In the first funding period among other novel gene defects (e.g. NEK10) we identified recessive TP73 and autosomal dominant de novo mutations in FOXJ1 causing RGMC with lissencephaly and hydrocephalus, respectively. Our previous studies indicated that in CCNO and MCIDAS mutant respiratory epithelia the number of basal bodies and cilia is severely reduced. While the number of basal bodies was not severely altered in TP73 and FOXJ1 mutant cells the number of cilia was reduced. Our analyses in airliquid interface cultures of TP73 mutant respiratory epithelia revealed that not only the process of ciliogenesis is affected, but also cell proliferation and or differentiation of the respiratory epithelia is altered. This is of high clinical importance because changes in cell composition enable a new deeper understanding of the underlying disease mechanisms. Within this project we will therefore further i. characterize the process of human multiciliogenesis, cell differentiation and cell proliferation in new and already known RGMC defects ii. perform identification and characterization of further RGMC individuals as well as novel genes related to RGMC using next generation sequencing approaches iii. perform genotype-phenotype analysis in RGMC affected.

多种活动纤毛排列在我们的呼吸道中，对清除上呼吸道和下呼吸道以防止感染和慢性炎症做出了重要贡献。我们已经能够描述一种新的粘液纤毛清除障碍组中的运动性纤毛病变：多发性运动性纤毛的减少生成(RGMC)。受影响的RGMC患有慢性破坏性呼吸道疾病。不幸的是，RGMC很难诊断，因为炎症引起的继发性改变可能与受影响的RGMC的呼吸道上皮细胞相似。在RGMC中，由于CCNO和MCIDAS的常染色体隐性突变，纤毛和/或纤毛细胞的形成明显减少。在第一个资助阶段，在其他新的基因缺陷(如NEK10)中，我们分别在FOXJ1中发现了隐性TP73突变和常染色体显性新基因突变，导致RGMC合并无脑畸形和脑积水。我们以前的研究表明，在CCNO和MCIDAS突变的呼吸道上皮细胞中，基底体和纤毛的数量严重减少。而TP73和FOXJ1突变细胞的基底体数目变化不大，纤毛数目减少。我们对TP73突变呼吸道上皮细胞气液界面培养的分析表明，不仅纤毛发生过程受到影响，而且呼吸上皮细胞的增殖和/或分化也发生了改变。这具有很高的临床重要性，因为细胞成分的变化使人们能够对潜在的疾病机制有新的更深入的了解。因此，在该项目中，我们将进一步I.在新的和已知的RGMC缺陷中表征人类多发性髂骨发生、细胞分化和细胞增殖的过程II。使用下一代测序方法III，对更多的RGMC个体以及与RGMC相关的新基因进行鉴定和表征。在受影响的RGMC中进行基因-表型分析。