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：
8655551
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/8655551
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 Functional RNA 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 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原发性纤毛中缺陷统一的疾病。临床表现范围从单个器官（最常见的后脑，肾脏，肝或眼睛）的主要参与到更严重的表现，例如梅克尔综合征，在几种器官中具有严重和多效性发育型表型。纤毛病疾病的几个基因已经并且继续被鉴定出来，绝大多数编码原发性纤毛的结构成分。控制纤毛依赖的信号传导和控制纤毛缺陷结果的调节基因的调节基因才开始与致病机制有关。该项目着重于控制睫状表型，ZFP423和未知的修饰基因。 ZFP423编码在多个信号转导途径和多个器官系统中所需的30锌指转录因子。缺乏ZFP423的动物具有明显的脑畸形，并且脑力较高，并且在几种外围组织中存在缺陷。幸存动物中表型的分布取决于修饰基因和显然是随机过程。但是，在最常用的菌株背景下，没有突变动物可以存活。遗传图标识了一个与胚胎和围产期致死性相关的单个主要基因座。该提案的目的将确定这种合成的致命修饰剂基因座，阐明其机制，并将其置于纤毛病网络中其他基因的背景下。