Synthetic Lethal Modifier of a New Ciliopathy Gene

新纤毛病基因的合成致死修饰剂

基本信息

批准号：
8845563
负责人：
BRUCE A HAMILTON
金额：
$ 30.23万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-27 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8845563
关键词：
Alleles Animals Benign Biological Brain Candidate Disease Gene Cellular Structures Cerebellar vermis structure Chromosome Mapping Cilia Clinical Clinical Investigator Code Collaborations Consomic Strain Data Defect Development Diploidy Disease Embryo Engineered Gene Event Eye Frequencies Gene Targeting Genes Genetic Genetic Drift Genetic Polymorphism Genetic Recombination Genetic Variation Haplotypes Human Hydrocephalus Inbred BALB C Mice Inbred Strain Inbreeding Individual Injection of therapeutic agent Joubert syndrome Kidney Knockout Mice Knowledge Laboratories Link Liver Lung Maps Mediating Modeling Molecular Molecular Genetics Mus Nephronophthisis Organ Orthologous Gene Outcome Patients Perinatal Peripheral Phenotype Physiological Rare Diseases Regulator Genes Resolution Resources Series Severities Signal Transduction Signal Transduction Pathway Staging Stochastic Processes Structure Syndrome Testing Therapeutic Tissues Transgenic Organisms Untranslated RNA Variant Work Zinc Fingers adult neurogenesis body system brain malformation ciliopathy clinically relevant congenic hindbrain human disease in vivo innovation insight mouse model mutant novel novel strategies prenatal tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): The ciliopathies comprise a spectrum of disorders unified by defects in primary cilia. Clinical presentations range from primary involvement of a single organ (most often hindbrain, kidney, liver or eye) to more severe presentations, such as Meckel syndrome, with severe and pleiotropic developmental phenotypes in several organs. Several genes have been and continue to be identified for ciliopathy disorders, with the overwhelming majority encoding structural components of primary cilia. Regulatory genes that control cilium-dependent signaling and modifier genes that control the outcome of ciliary defects are only beginning to be tied to pathogenic mechanisms. This project focuses on the synthetic lethal interaction between a transcriptional regulator that control ciliary phenotypes, Zfp423, and an unknown modifier gene. Zfp423 encodes a 30-zinc finger transcription factor required in several signal transduction pathways and in multiple organ systems. Animals that lack Zfp423 have prominent brain malformations with a high frequency of hydrocephalus as well as defects in several peripheral tissues. The distribution of phenotypes in surviving animals is dependent on both modifier genes and apparently stochastic processes. However, on the most commonly used strain background, no mutant animals survive. Genetic mapping identifies a single major locus linked to embryonic and perinatal lethality. The aims of this proposal will identify this synthetic lethal modifier locus, elucidate its mechanism and place it in the context of other genes in the ciliopathy network.

描述（由申请人提供）：纤毛病包括一系列由初级纤毛缺陷统一的疾病。临床表现范围从单一器官的原发性受累（最常见的是后脑、肾脏、肝脏或眼睛）到更严重的表现，例如梅克尔综合征，在多个器官中具有严重的多效性发育表型。已经并将继续鉴定出一些与纤毛病有关的基因，其中绝大多数编码初级纤毛的结构成分。控制纤毛依赖性信号传导的调节基因和控制纤毛缺陷结果的修饰基因才刚刚开始与致病机制联系起来。该项目重点关注控制纤毛表型的转录调节因子 Zfp423 和未知的修饰基因。 Zfp423 编码多种信号转导途径和多个器官系统所需的 30 锌指转录因子。缺乏 Zfp423 的动物具有明显的脑畸形，脑积水发生率高，并且多个外周组织存在缺陷。幸存动物的表型分布取决于修饰基因和明显的随机过程。然而，在最常用的菌株背景下，没有突变动物能够存活。基因图谱确定了与胚胎和围产期死亡率相关的一个主要基因座。该提案的目的是确定这种合成致死修饰基因座，阐明其机制并将其置于纤毛病网络中其他基因的背景下。