A Model for Nephronophthisis in Caenorhabditis elegans

秀丽隐杆线虫肾结核模型

• 批准号: 8143427
• 负责人: MAUREEN M BARR
• 金额: $ 31.08万
• 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 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8143427
• 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. 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.

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的最常见遗传原因。 NPHP 是由至少 9 个不同基因 (NPHP1 - NPHP9) 之一的突变引起的，占 NPHP 病例的不到 50%，这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（肾囊肿素）定位于纤毛，但它们在这种感觉细胞器中的功能仍然很大程度上未知。线虫秀丽隐杆线虫是研究肾囊肿素在其天然细胞环境中的作用的强大模型生物。在秀丽隐杆线虫中，NPHP-1 和 NPHP-4 以细胞类型特异性方式全局调节纤毛发育和形态发生。人和蠕虫的 nephrocystin-1 和 nephrocystin-1 分别定位于肾上皮细胞和感觉神经元上纤毛的过渡区，表明其作用在进化上是保守的。目标 1 中拟议的研究将定义 NPHP-1 和 NPHP-4 如何在睫状过渡区发挥作用。目标 2 中拟议的研究将确定线虫 NPHP2、NPHP8 和 NPHP9 同源物的作用。目标 3 中拟议的研究将揭示 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。对肾痨等人类纤毛疾病的了解依赖于对纤毛成分以及与修饰基因座的复杂遗传和发育相互作用的完整了解。这些拟议的研究将扩大我们在遗传、分子、细胞和有机体水平上对肾囊肿素和纤毛生物学的理解。这种理解对于确定 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至关重要。 公共健康相关性：纤毛是几乎所有非分裂人类细胞中都存在的运动或感觉细胞器。纤毛发育的机制在藻类、蠕虫、苍蝇、鱼、小鼠和人类等生物体中是进化保守的。最近的研究表明，纤毛缺陷与人类囊性肾病有关，如肾痨 (NPHP)、常染色体显性多囊肾病 (ADPKD)、常染色体隐性遗传性 PKD、Bardet-Biedl 综合征 (BBS) 和 Meckel Gruber 综合征 (MKS)。线虫秀丽隐杆线虫是研究纤毛相关人类疾病基因的特殊动物模型系统。秀丽隐杆线虫纤毛的形成、维持和功能所需的许多基因在人类中都有对应的基因，当这些基因发生突变时，会导致肾脏病变疾病。该研究旨在利用线虫强大的分子遗传学工具来模拟肾痨，这是婴儿、儿童和年轻人终末期肾病的最常见遗传原因。