A Model for Nephronophthisis in Caenorhabditis elegans

秀丽隐杆线虫肾结核模型

• 批准号: 8717637
• 负责人: MAUREEN M BARR
• 金额: $ 31.39万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2015-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8717637
• 关键词: Accounting; Address; Afferent Neurons; Algae; Animal Model; Autosomal Dominant Polycystic Kidney; Bardet-Biedl Syndrome; Biological Models; Biology; Body Regions; Caenorhabditis elegans; Cells; Child; Chlamydomonas; Cilia; Clinical; Complex; Cystic Kidney Diseases; Defect; Development; Disease; End stage renal failure; Environment; Epithelial Cells; Exhibits; Fiber; Fishes; Genes; Genetic; Homologous Gene; Human; Infant; Kidney; Kidney Diseases; Length; Link; Maintenance; Modeling; Molecular Genetics; Morphogenesis; Mus; Mutate; Mutation; Nematoda; Nephronophthisis; Organelles; Organism; PKD2 protein; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Physiological; Process; Protein Isoforms; Proteins; Regulation; Retinitis Pigmentosa; Role; Sensory; Shipping; Ships; Signal Transduction; Syndrome; System; Testing; Transmission Electron Microscopy; Vanilloid; base; cell type; ciliopathy; cilium biogenesis; design; developmental genetics; fly; genetic analysis; human disease; kinetosome; loss of function; mutant; parkin gene/protein; public health relevance; receptor; therapeutic target; tool; young adult

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.

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。