Zfp423 Mechanisms in Joubert Syndrome and Related Disorders

Zfp423 Joubert 综合征及相关疾病的机制

基本信息

批准号：
10522573
负责人：
BRUCE A HAMILTON
金额：
$ 55.27万
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：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10522573
关键词：
Animal Genetics Animal Model Animals Architecture Binding Proteins Biological Assay Brain CRISPR interference Cell Lineage Cell Proliferation Cell model Cells Cerebellar vermis structure Cilia Clinical Complex Conflict (Psychology)Cues Cytoplasmic Granules Data Defect Development Differentiation Antigens Disease Environment Family Frequencies Gene-Modified Genes Genetic Genetic Transcription Heterozygote Homozygote Human Individual Intervention Joubert syndrome Ligands Mediating Modeling Molecular Genetics Mus Mutant Strains Mice Mutation Nephronophthisis Neuronal Differentiation Nuclear Organ Outcome Pathogenicity Pathway interactions Patients Pattern Phenotype Population Proteins Rare Diseases Regulator Genes Reporting Reproducibility Retinoic Acid Receptor Role SHH gene Signal Pathway Signal Transduction Structure Testing Transcription Regulatory Protein Tretinoin Undifferentiated Variant Zinc Fingers base brain abnormalities brain malformation ciliopathy developmental disease developmental neurobiology extracellular genetic testing granule cell hindbrain improved in vivo innovation malformation morphogens mouse model mutant notch protein precursor cell progenitor programs response single-cell RNA sequencing stem cells tool transcription factor

项目摘要

Project Summary: This project develops cell and animal models to understand the role of a multivalent transcription factor, ZNF423, in integrating information from extracellular signaling and intracellular lineage pathways during hindbrain development. ZNF423 encodes a constitutively nuclear transcriptional regulatory protein that binds lineage differentiation factors of the EBF family and transcriptional effectors for canonical signling pathways, including SMAD, retinoic acid, and NOTCH intracellular domains. ZNF423 mutations are reported in rare Joubert syndrome (JBTS19) and nephronophthisis (NPHP14) ciliopathy patients. The ciliopathies comprise a broad family of individually rare disorders unified by signaling defects in primary cilia. Clinical presentations range mild to lethal and from primary involvement of a single organ to more pleiotropic presentations. The overwhelming majority of genes identified for ciliopathy disorders encode physical components of primary cilia. Regulatory genes that control cilium-dependent signaling and genetic modifiers that change the outcome of ciliary defects remain understudied with respect to pathogenic mechanisms and potential points for intervention in more typical cases. ZNF423 is thought to comprise an integrative node among several transcriptional complexes that respond to classical intercellular signals during brain development and to regulate SHH signaling through the primary cilium. Both reported patients and mouse models show hindbrain malformations that include hypoplasia or agenesis of the vermis. Aim 1 will test hypotheses for ZNF423 activity in canalizing information from complex signaling environments into predictable cell responses. Aim 2 will comprehensively test for modifier genes that alter cellular outcomes ex vivo in response to loss of ZNF423. Aim 3 will test hypotheses for ZNF423 participation in oligogenic brain malformations in a well-validated animal model.

项目概要：该项目开发细胞和动物模型来了解多价转录因子的作用， ZNF423，在整合细胞外信号传导和细胞内谱系途径的信息时后脑发育。 ZNF423 编码一种组成型核转录调节蛋白，结合 EBF 家族的谱系分化因子和经典信号转导的转录效应子途径，包括 SMAD、视黄酸和 NOTCH 细胞内结构域。 ZNF423 突变是在罕见的 Joubert 综合征 (JBTS19) 和肾结核 (NPHP14) 纤毛病患者中有报道。这纤毛病包括一系列单独罕见的疾病，这些疾病通过信号缺陷统一起来初级纤毛。临床表现范围从轻度到致命，从单一器官的主要受累更多的多效性演示。绝大多数已被鉴定为纤毛病基因编码初级纤毛的物理成分。控制纤毛依赖性的调节基因改变纤毛缺陷结果的信号传导和遗传修饰剂仍未得到充分研究关于更典型病例的致病机制和潜在干预点。 ZNF423 被认为包含多个转录复合物之间的整合节点，对大脑发育过程中的经典细胞间信号做出反应并调节 SHH 信号传导通过初级纤毛。报道的患者和小鼠模型均显示后脑畸形包括蚓部发育不全或发育不全。目标 1 将测试 ZNF423 活性的假设将复杂信号环境中的信息转化为可预测的细胞反应。目标2将全面测试修饰基因，这些修饰基因会在体外改变细胞结果，以响应失去 ZNF423。目标 3 将测试 ZNF423 参与寡基因脑畸形的假设经过充分验证的动物模型。