Novel genetics, pathobiology & therapy of nephronophthisis-related ciliopathies

新遗传学、病理学

• 批准号: 8067119
• 负责人: FRIEDHELM HILDEBRANDT
• 金额: $ 30.82万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067119
• 关键词: Affect; Alleles; Animal Model; Award; Blindness; Cell Cycle; Cell Cycle Regulation; Cell Polarity; Centrosome; Characteristics; Chronic Kidney Failure; Cilia; Cystic Kidney Diseases; Data; Degenerative Disorder; Development; Disease; Disease model; Dysplasia; Esthesia; Evolution; Family; Gene Mutation; Genes; Genetic; Genotype; Heart; Hormonal; Human; Individual; Kidney Failure; Large-Scale Sequencing; Life; Liver Fibrosis; Maintenance; Maps; Mental Retardation; Missense Mutation; Mitotic spindle; Modeling; Morphogenesis; Mus; Mutate; Mutation; Nephronophthisis; Organ; Organelles; Organism; Pathogenesis; Pharmaceutical Preparations; Phenotype; Premature aging syndrome; Proteins; Retinal; Retinal Degeneration; Sensory; Signal Pathway; Signal Transduction; Syndrome; Testing; Therapeutic; Tissues; Zebrafish; animal model development; bone; brain malformation; cell type; ciliopathy; cohort; disease phenotype; drug candidate; drug testing; early onset; exome; human disease; insight; loss of function; malformation; novel; novel therapeutic intervention; pleiotropism; protein complex; protein protein interaction; public health relevance; repaired; smoothened signaling pathway

DESCRIPTION (provided by applicant): Nephronophthisis (NPHP) is a monogenic recessive cystic kidney disease that represents the most frequent genetic cause of kidney failure in the first 30 years of life. It can be associated with progressive blindness (retinal degeneration), liver fibrosis, mental retardation and malformations of brain, heart and bone. By homozygosity mapping we have previously identified recessive mutations in 4 genes (NPHP1-4) as the cause of NPHP with retinal involvement. Within the preceding award we identified and characterized 5 additional NPHP-causing genes (NPHP5-9) and generated disease models in mouse and zebrafish. The data helped define a unifying pathogenic concept for the new disease entity of "ciliopathies", which represent genetic defects in functional components of primary cilia (PC). PC are sensory organelles expressed by virtually all vertebrate cell types. PC are utilized across evolution, from single cellular organisms to humans, for cellular sensory tasks, including photo-, mechano-, thermo-, olfactory, and hormonal sensation. By identification of the NPHP1-9 genes we implicated non-canonical Wnt signaling, hedgehog signaling, and cell cycle regulation in the pathogenesis of cystic kidney diseases. In addition, we demonstrated that specific mutated alleles determine the disease phenotype of NPHP-related ciliopathies in the following way: Two truncating mutations cause a severe, early- onset developmental phenotype that affects morphogenesis and leads to malformation or dysplasia (Meckel- Gruber syndrome), whereas two missense mutations cause only a mild, late-onset mature tissue phenotype that affects tissue maintenance and repair and leads to degeneration and premature ageing of organs (Senior- Loken syndrome). We demonstrate in a worldwide cohort of 1,500 families with NPHP-related ciliopathies that mutations in NPHP1-9 only explain 30% of all cases and that many additional disease causing genes must exist. To discover new ciliopathy genes and the associated signaling mechanisms, and to generate animal models and therapeutic options, we propose to: 1. Identify and functionally characterize novel genes that cause NPHP-related ciliopathies, if mutated. 2. Functionally characterize novel ciliopathy genes and determine genotype-phenotype correlations. 3. Use zebrafish models to study the function of novel genes identified and to test new drugs. PUBLIC HEALTH RELEVANCE: Nephronophthisis (NPHP), a genetic cause of chronic kidney disease, is associated with blindness, liver fibrosis, and organ malformations. No specific treatment is available. Previous gene identification helped define the new disease group of "ciliopathies," caused by loss of function of primary cilia, which are sensory organelles important for photo-, mechano-, and olfactory sensation and for tissue development and repair. Identification of novel NPHP-related ciliopathy genes will provide further insights into disease mechanisms of dysplastic and degenerative diseases of multiple organs. It will allow development of animal models and novel therapeutic approaches to these degenerative diseases.

描述（由申请人提供）：肾植物（NPHP）是一种单身性隐性囊性肾脏疾病，代表了生命的头30年中肾衰竭最常见的遗传原因。它可能与进行性失明（视网膜变性），肝纤维化，智力低下和大脑，心脏和骨骼的畸形有关。通过纯合性映射，我们以前已经确定了4个基因（NPHP1-4）中隐性突变为视网膜受累的NPHP的原因。在上一项奖项中，我们确定并表征了5个其他引起NPHP的基因（NPHP5-9），并在小鼠和斑马鱼中产生的疾病模型。该数据有助于为“纤毛病”的新疾病实体定义了一个统一的致病概念，该疾病代表原发性纤毛（PC）功能成分的遗传缺陷。 PC是几乎所有脊椎动物细胞类型表达的感觉细胞器。 PC在进化中被用于从单个细胞生物到人类，用于细胞感觉任务，包括光，机械，热，嗅觉和激素感觉。通过鉴定NPHP1-9基因，我们与囊性肾脏疾病的发病机理中有关非经典Wnt信号传导，刺猬信号传导和细胞周期调节。此外，我们证明了特定的突变等位基因通过以下方式决定了与NPHP相关的纤毛病的疾病表型：两个截短突变导致严重的，早期发作的发育表型，影响形态发生并影响形态发生并导致畸形或发育不良（麦克氏 - 格鲁伯综合症），并导致两种疾病的疾病，而后期的疾病是一种疾病，结局是一种疾病，概念的现实 - 概念概念，概念概念，造成了现实，并引起了疾病的现象，并导致了现实的现实，并导致了畸形或增生。维护和维修，并导致器官（高级综合症）的变性和过早衰老。我们在全球1,500个与NPHP相关的纤毛病的家庭中证明，NPHP1-9中的突变仅解释了所有病例中的30％，并且必须存在许多其他引起基因的疾病。为了发现新的纤毛病基因和相关的信号传导机制，并生成动物模型和治疗选择，我们建议：1。识别并在功能上表征引起NPHP相关的纤毛病的新型基因，如果突变。 2。在功能上表征了新型的纤毛病基因并确定基因型 - 表型相关性。 3。使用斑马鱼模型研究已鉴定出的新型基因的功能并测试新药。 公共卫生相关性：肾植物（NPHP）是慢性肾脏疾病的遗传原因，与失明，肝纤维化和器官畸形有关。没有特定的治疗方法。先前的基因鉴定有助于定义新的“纤毛病”疾病组，这是由于原发性纤毛功能的丧失而引起的，这对于光，机械和嗅觉感觉以及组织的发育和修复至关重要。新型NPHP相关的纤毛病基因的鉴定将为多个器官的发育异常和退化性疾病的疾病机制提供进一步的见解。它将允许开发动物模型和新的治疗方法来解决这些退化性疾病。