A Model for Nephronophthisis in Caenorhabditis elegans

描述（由申请人提供）：肾结核是一种常染色体隐性遗传性肾病，是儿童和年轻人终末期肾病的最常见遗传原因。肾结核是由至少五个基因之一的突变引起的，NPHP 1-NPHP 5。常染色体显性遗传性多囊肾病（ADPKD）和其他人类囊性肾病与纤毛缺陷有关。NPHP蛋白产物（肾囊蛋白）定位于纤毛，但几乎没有什么是已知的细胞和分子功能，这些重要的蛋白质。线虫秀丽隐杆线虫提供了显着的实验优势，在其原生细胞环境中的肾胱氨酸的生理作用的特点。我们已经开发并建立了蠕虫作为NPHP的模型。我们发现nphp-1和nphp-4在纤毛感觉神经系统中表达，并与C. elegans ADPKD基因lov-1/PC-1和pkd-2/PC-2。与人肾囊蛋白类似，GFP标记的NPHP-1和NPHP-4蛋白定位于纤毛。与感觉的作用一致，我们发现nphp-1和nphp-4缺失突变体形成纤毛，但在几种感觉行为中有缺陷，包括雄性交配和dauer形成。我们提出并将测试三种模型肾囊蛋白功能。在第一种模型中，肾囊蛋白发挥结构作用并调节纤毛发育或形态发生。在第二个模型中，肾囊蛋白在纤毛蛋白转运中起作用。在最终的模型中，肾胱氨酸以信号传导能力起作用，以介导纤毛内或来自纤毛的感觉转导。纤毛定位的NPHP和ADPKD蛋白的高度物种保守性使得这些在C.秀丽隐杆线虫将有助于阐明肾胱氨酸蛋白在正常和病理疾病状态下如何在人类肾脏中起作用。本研究的结果将为肾囊蛋白的功能、蛋白质转运、感觉信号转导和人类睫状体疾病的研究提供有价值的信息。

DESCRIPTION (provided by applicant): Nephronophthisis is an autosomal recessive kidney disease and the most common genetic cause of end-stage renal disease in children and young adults. Nephronophthisis is caused by mutation in one of at least five genes, NPHP1 - NPHP5. NPHP, autosomal dominant polycystic kidney disease (ADPKD) and other human cystic kidney diseases have been associated with defects in cilia. The NPHP protein products (the nephrocystins) localize to cilia, but almost nothing is known about the cellular and molecular functions of these important proteins. The nematode Caenorhabditis elegans offers significant experimental advantages for characterizing the physiological roles of the nephrocystins in their native cellular environments. We have developed and established the worm as a model for NPHP. We showed that nphp-1 and nphp-4 are expressed in ciliated sensory nervous system and are coexpressed with the C. elegans ADPKD genes lov-1/PC-1 and pkd-2/PC-2. Similar to the human nephrocystins, GFP-tagged NPHP-1 and NPHP-4 proteins localize to cilia. Consistent with a role in sensation, we found that nphp-1 and nphp-4 deletion mutants form cilia but are defective in several sensory behaviors, including male mating and dauer formation. We propose and will test three models for nephrocystin function. In the first model, the nephrocystins play a structural role and regulate cilia development or morphogenesis. In the second model, the nephrocystins function in ciliary protein transport. In the final model, the nephrocystins act in a signaling capacity to mediate sensory transduction within or from the cilium. The high level of species conservation of ciliary-localized NPHP and ADPKD proteins makes it likely that these studies in C. elegans will help elucidate how the nephrocystins work in the human kidney in normal and pathological disease states. The results of this proposal will provide valuable insight into several areas, including the functions of the nephrocystins, protein transport, sensory signaling transduction, and human ciliary diseases.