A Model for Nephronophthisis in Caenorhabditis elegans

描述（由申请人提供）：肾脏病（NPHP）是婴儿、儿童和年轻人终末期肾脏疾病最常见的遗传原因。NPHP是由至少9个不同基因（NPHP1 - NPHP9）中的一个突变引起的，占NPHP病例的不到50%，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（肾囊素）定位于纤毛，但它们在纤毛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素在其原生细胞环境中作用的有力模式生物。在秀丽隐杆线虫中，NPHP-1和NPHP-4以细胞类型特异性的方式调控纤毛的发育和形态发生。人和蠕虫的肾囊素-1和肾囊素-1分别定位于肾上皮细胞和感觉神经元的纤毛过渡区，提示其在进化上的保守作用。Aim 1中提出的研究将确定NPHP-1和NPHP-4如何在纤毛过渡区发挥作用。Aim 2中提出的研究将确定秀丽隐杆线虫NPHP2、NPHP8和NPHP9同源物的作用。Aim 3中提出的研究将揭示NPHP基因与已知纤毛病基因同源物之间的遗传和功能相互作用。了解人类纤毛疾病，如肾结石，依赖于对纤毛成分的全面了解，以及与修饰位点复杂的遗传和发育相互作用。这些建议的研究将扩大我们对肾囊素和纤毛生物学在遗传、分子、细胞和有机体水平上的理解。为了确定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，这种理解是必不可少的。

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.