A Model for Nephronophthisis in Caenorhabditis elegans

描述(申请人提供)：肾单位(NPHP)是导致婴儿、儿童和年轻人终末期肾脏疾病的最常见的遗传原因。NPHP是由至少九个不同基因(NPHP1-NPHP9)中的一个突变引起的，在NPHP病例中所占比例不到50%，表明许多其他疾病位点仍未确定。NPHP和其他囊性肾脏疾病与纤毛缺陷有关。虽然NPHP基因产物(肾囊素)定位于纤毛，但它们在这个感觉器中的功能仍然很大程度上是未知的。线虫秀丽线虫是研究肾囊毒素在其天然细胞环境中作用的有力模式生物。在线虫中，NPHP-1和NPHP-4以细胞类型特异性的方式全局作用于纤毛发育和形态发生。人和虫的肾囊藻毒素-1和肾囊藻毒素-1分别定位于肾上皮细胞和感觉神经元上的纤毛过渡区，提示在进化上具有保守的作用。目标1中拟议的研究将定义NPHP-1和NPHP-4如何在纤毛过渡区发挥作用。目标2中提议的研究将确定线虫NPHP2、NPHP8和NPHP9同源物的作用。在AIM 3中提出的研究将揭示NPHP基因和已知的睫状病基因同源物之间的遗传和功能相互作用。对人类纤毛疾病的理解，如肾单位病，依赖于对纤毛成分以及复杂的遗传和发育与修饰性基因座相互作用的完整了解。这些拟议的研究将在遗传、分子、细胞和生物水平上拓宽我们对肾囊藻毒素和纤毛生物学的理解。这样的了解对于确定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是至关重要的。 与公共卫生相关：纤毛是一种运动或感觉器，几乎存在于所有未分裂的人类细胞中。纤毛发育的机制在进化上是保守的，存在于从藻类、蠕虫、苍蝇、鱼、老鼠到人类的各种生物中。最近的研究表明纤毛缺陷与人类囊性肾脏疾病有关，如肾单位肾炎(NPHP)、常染色体显性遗传性多囊肾病(ADPKD)、常染色体隐性遗传性PKD、Bardet-Biedl综合征(BBS)和Meckel Gruber综合征(MKS)。秀丽线虫是研究纤毛相关人类疾病基因的特殊动物模型系统。线虫纤毛的形成、维持和功能所需的许多基因都与人类同源，当突变时，会导致肾脏病理疾病。这项研究旨在使用线虫强大的分子遗传学工具来模拟肾炎，这是婴儿、儿童和年轻人终末期肾脏疾病最常见的遗传原因。

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.