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.

多个活动纤毛排列在我们的呼吸道中，对清理上呼吸道和下呼吸道以预防感染和慢性炎症做出了重要贡献。我们已经能够描述粘液纤毛清除障碍组中的一种新型运动纤毛病：多运动纤毛（RGMC）生成减少。受影响的 RGMC 患有慢性破坏性气道疾病。不幸的是，RGMC 很难诊断，因为炎症引起的继发性变化可能与受影响的 RGMC 呼吸道上皮细胞中看到的情况相似。在 RGMC 中，由于 CCNO 和 MCIDAS 的常染色体隐性突变，纤毛和/或纤毛细胞的形成显着减少。在第一个资助期间，在其他新的基因缺陷（例如 NEK10）中，我们发现了隐性 TP73 和 FOXJ1 中的常染色体显性从头突变，分别导致 RGMC 伴有无脑畸形和脑积水。我们之前的研究表明，在 CCNO 和 MCIDAS 突变的呼吸道上皮细胞中，基体和纤毛的数量严重减少。虽然 TP73 和 FOXJ1 突变细胞中基体的数量没有严重改变，但纤毛的数量却减少了。我们对 TP73 突变体呼吸道上皮细胞的气液界面培养物的分析表明，不仅纤毛发生过程受到影响，而且呼吸道上皮细胞的增殖和/或分化也发生了改变。这具有很高的临床重要性，因为细胞组成的变化使人们能够更深入地了解潜在的疾病机制。因此，在这个项目中，我们将进一步 i。 ii. 描述新的和已知的 RGMC 缺陷中人类多纤毛发生、细胞分化和细胞增殖的过程。使用下一代测序方法对更多 RGMC 个体以及与 RGMC 相关的新基因进行鉴定和表征 iii。对受影响的 RGMC 进行基因型-表型分析。