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.

项目摘要：该项目开发细胞和动物模型，以了解多价转录因子的作用， ZNF423，在整合来自细胞外信号传导和细胞内谱系途径的信息中后脑发展。 ZNF423编码一种组成性核转录调节蛋白绑定EBF家族的谱系分化因子和典型签名的转录效应子途径，包括Smad，视黄酸和缺口细胞内结构域。 Znf423突变是报道了罕见的乔伯特综合征（JBTS19）和肾植物（NPHP14）纤毛病患者。这纤毛病包括一个由信号缺陷统一的广泛的罕见疾病家庭原发性纤毛。临床演示范围轻度到致死，并且来自单个器官的主要参与进行更多的多效性演示。绝大多数针对纤毛病疾病的基因编码主要纤毛的物理成分。控制纤毛依赖性的调节基因改变睫状缺陷结果的信号传导和遗传修饰符仍在研究在更典型的情况下，针对病原机制和干预的潜在点。 Znf423被认为包括几个转录复合物中的一个集成节点在大脑发育过程中响应经典的细胞间信号并调节SHH信号通过原发性纤毛。报告的患者和小鼠模型都表现出后脑畸形其中包括发育不全或vermis的发育不全。 AIM 1将测试Znf423活性的假设将复杂信号环境的信息载入可预测的细胞响应。 AIM 2意志全面测试因损失而改变细胞结果的修饰基因 ZNF423。 AIM 3将测试ZnF423参与寡聚性脑畸形的假设验证的动物模型。