A Model for Nephronophthisis in Caenorhabditis elegans

描述（由申请人提供）：肾痨（NPHP）是婴儿、儿童和年轻人终末期肾病最常见的遗传原因。NPHP是由至少9种不同基因（NPHP 1-NPHP 9）中的一种突变引起的，占NPHP病例的不到50%，并表明许多其他疾病位点仍未确定。NPHP和其他囊性肾病与纤毛缺陷有关。虽然NPHP基因产物（肾囊蛋白）定位于纤毛，但它们在这种感觉细胞器中的功能在很大程度上仍然未知。秀丽隐杆线虫是研究肾囊蛋白在其天然细胞环境中的作用的一种强有力的模式生物。In C.在线虫中，NPHP-1和NPHP-4以细胞类型特异性方式全面调节纤毛发育和形态发生。人类和蠕虫肾囊蛋白-1和肾囊蛋白-1定位于肾上皮细胞和感觉神经元上的纤毛的过渡区，分别表明进化保守的作用。目标1中提出的研究将定义NPHP-1和NPHP-4如何在纤毛过渡区发挥作用。目标2中提出的研究将确定C。线虫NPHP 2、NPHP 8和NPHP 9同源物。目标3中提出的研究将揭示NPHP基因与已知纤毛疾病基因同源物之间的遗传和功能相互作用。人类睫状体疾病，如肾结石的理解依赖于睫状体成分和复杂的遗传和发育的相互作用与修饰基因座的完整理解。这些拟议的研究将扩大我们的理解肾囊蛋白和纤毛生物学在遗传，分子，细胞和有机体水平。这样的理解是必不可少的，以确定NPHP基因的功能，它们在疾病过程中的作用，以及它们作为治疗靶点的潜力。 纤毛是一种运动或感觉细胞器，几乎存在于每一个不分裂的人类细胞中。纤毛发育的机制在从昆虫、蠕虫、苍蝇、鱼、小鼠到人类的生物体中是进化上保守的。最近的研究表明，纤毛缺陷与人类囊性肾病有关，例如肾痨（NPHP）、常染色体显性多囊肾病（ADPKD）、常染色体隐性PKD、Bardet-Biedl综合征（BBS）和Meckel Gruber综合征（MKS）。秀丽隐杆线虫是研究纤毛相关人类疾病基因的一种特殊的动物模型系统。许多基因的形成，维持和功能的C。秀丽线虫的纤毛在人类中有对应物，当突变时，会引起肾脏病变。这项研究旨在利用C.线虫来模拟肾痨，这是婴儿、儿童和年轻人中终末期肾病的最常见遗传原因。

DESCRIPTION (provided by applicant): Nephronophthisis (NPHP) is the most common genetic cause of end stage renal disease in infants, children, and young adults. NPHP is caused by a mutation in one of at least nine different genes (NPHP1 - NPHP9), accounting for less than 50% NPHP cases and indicating that many other disease loci remain unidentified. NPHP and other cystic kidney diseases are associated with defects in cilia. While the NPHP gene products (the nephrocystins) are localized to cilia, their functions in this sensory organelle remain largely unknown. The nematode Caenorhabditis elegans is a powerful model organism to study the roles of the nephrocystins in their native cellular environment. In C. elegans, NPHP-1 and NPHP-4 act globally to modulate ciliary development and morphogenesis in a cell-type specific manner. Human and worm nephrocystin-1 and nephrocystin-1 localize to the transition zone of cilia on renal epithelial cells and sensory neurons, respectively, suggesting an evolutionarily conserved role. Proposed studies in Aim 1 will define how NPHP-1 and NPHP-4 function at the ciliary transition zone. Proposed studies in Aim 2 will determine the role of the C. elegans NPHP2, NPHP8, and NPHP9 homologs. Proposed studies in Aim 3 will reveal genetic and functional interactions between the NPHP genes and known ciliopathy disease gene homologs. An understanding of human ciliary diseases such as Nephronophthisis relies on a complete understanding of ciliary components and of complex genetic and developmental interactions with modifier loci. These proposed studies will broaden our understanding of the nephrocystins and cilia biology at the genetic, molecular, cellular, and organismal levels. Such understanding is essential in order to identify the functions of the NPHP genes, their role in disease processes, and their potential as therapeutic targets. PUBLIC HEALTH RELEVANCE: Cilia are motile or sensory organelles found on almost every non-dividing human cell. The mechanism of ciliary development is evolutionarily conserved in organisms ranging from alga, worms, flies, fish, mouse, to human. Recent studies have revealed that defects in cilia are linked to human cystic kidney diseases such as Nephronophthisis (NPHP), autosomal dominant polycystic kidney disease (ADPKD), autosomal recessive PKD, Bardet-Biedl Syndrome (BBS), and Meckel Gruber Syndrome (MKS). The nematode Caenorhabditis elegans is an exceptional animal model system for the study of cilia-related human disease genes. Many of the genes required for the formation, maintenance, and function of C. elegans cilia have human counterparts that, when mutated, cause diseases with renal pathologies. The study is designed to use the powerful molecular genetic tools of C. elegans to model Nephronophthisis, the most common genetic cause of end stage renal disease in infants, children, and young adults.