Characterization of novel single gene causes of nephrotic syndrome in Drosophila

果蝇肾病综合征新单基因病因的表征

• 批准号: 277333950
• 负责人: Privatdozent Dr. Tobias Hermle
• 金额: --
• 依托单位: Klinik für Innere Medizin IV - Nephrologie und Allgemeinmedizin
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/277333950?language=en
• 关键词: Characterization; novel; single; gene; causes

Steroid-resistant nephrotic syndrome is a frequent cause of chronic kidney disease and curative treatment is lacking. In a large proportion of cases the etiology is genetic. More than 30 monogenetic causes have been identified with a major contribution from the Hildebrandt lab (Boston Children´s Hospital/Harvard Medical School). In another 19 genes an insufficient number of affected families have been found, so the data are currently insufficient. However, mutations in single gene disorders are commonly rare and several of these genes most likely play a role in the pathogenesis of nephrotic syndrome. Recent findings indicate a surprising similarity between the Drosophila Nephrocyte and the glomerular filtration apparatus. This allows an analysis of such disease genes in the Drosophila model. The endocytic activity of Nephrocytes can be visulized by the uptake of fluorescently labelled macromolecules like Texas-Red-Avidin. This renders information about the state of the Nephrocyte diaphragm that corresponds to the slit diaphragm. Directed RNAi-expression in Nephrocytes thus allows screening of the Drosophila Homologs available for 16 of the 19 human genes. The function of one or several of the confirmed genes could be characterized in more detail in Drosophila. The wide array of genetic tools in Drosophila could be employed to this end. Finally, findings could be verified by focused analysis in the mouse model. These efforts will most likely deliver new insight into the pathgenesis of nephrotic syndrome.

类固醇抵抗性肾病综合征是慢性肾脏疾病的常见原因，并且缺乏治愈性治疗。在很大一部分病例中，病因是遗传的。Hildebrandt实验室（波士顿儿童医院/哈佛医学院）的主要贡献已经确定了30多个单基因原因。在另外19个基因中，发现受影响的家庭数量不足，因此目前的数据不足。然而，单基因疾病的突变通常是罕见的，其中几个基因最有可能在肾病综合征的发病机制中发挥作用。最近的研究结果表明，果蝇肾细胞和肾小球滤过装置之间惊人的相似性。这允许在果蝇模型中分析此类疾病基因。肾细胞的内吞活性可以通过摄取荧光标记的大分子如德克萨斯红-抗生物素蛋白来可视化。这呈现了关于对应于狭缝光阑的肾细胞光阑的状态的信息。因此，肾细胞中的定向RNAi表达允许筛选可用于19个人类基因中的16个的果蝇同源物。一个或几个已证实的基因的功能可以在果蝇中更详细地描述。果蝇中广泛的遗传工具可以用于这一目的。最后，研究结果可以通过在小鼠模型中的集中分析来验证。这些努力将很可能为肾病综合征的发病机制提供新的见解。