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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：
9418651
负责人：
BRUCE A HAMILTON
金额：
$ 34.99万
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 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9418651
关键词：
Affect Alleles Animal Model Animals Antibodies Biological Assay C2H2 Zinc Finger Cell Culture Techniques Cell model Cells Cerebellar vermis structure Characteristics Chromosomes, Human, Pair 8 Cilia Clinical Complex DNA Binding Data Defect Development Disease Epigenetic Process Eye Frequencies Genes Genetic Genetic Diseases Genetic Transcription Heterogeneity Human In Situ Individual Joubert syndrome Kidney Knockout Mice Liver Mediating Mitotic Mitotic Recombination Modeling Molecular Morphology Mosaicism Mus Mutate Mutation Nephronophthisis Nuclear Nuclear Protein Organ Organelles Outcome Pathogenesis Pathogenicity Patients Phenotype Proteins RNA Interference Regulation Regulator Genes Reporting Role SHH gene Severities Signal Pathway Signal Transduction Syndrome Testing Transcription Regulatory Protein Transfection Variant Work base ciliopathy disease phenotype exome sequencing genetic regulatory protein genome editing granule cell hindbrain improved in vivo knock-down mouse genome mouse model mutant non-genetic overexpression protein protein interaction response tool trafficking transcription factor transcriptome sequencing

项目摘要

Project Summary: This project focuses on cellular, genetic, and molecular mechanisms that underlie developmental abnormalities in ZNF423-realted ciliopathy. 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 identified for ciliopathy disorders, with the overwhelming majority encoding physical components of primary cilia. Regulatory genes that control cilium-dependent signaling and genetic modifiers that control the outcome of ciliary defects are only beginning to be tied to pathogenic mechanisms. This project focuses on the role and mechanisms of ZNF423, a constitutively nuclear transcriptional regulatory protein mutated in Joubert syndrome (JBTS19) and nephronophthisis (NPHP14) patients. ZNF423 is thought to comprise an integrative node among several transcriptional complexes that respond to classical developmental signals. As ZNF423 expression is also developmentally dynamic, the extent to which phenotypes are cell autonomous, rather than defects in reciprocal intercellular signaling, remains unclear. Aim 1 will use recently developed genetic tools (MADM) to assess cell autonomy by creating a simple platform for inducing and marking mitotic clones in situ. Because patient mutations are individually rare, often found on only one allele, and found in subjects with a range of presentations, it remains unclear what fraction of patients is attributable to ZNF423 and which ZNF423 mutations are truly pathogenic. Aim 2 will use genome editing in a sensitive and well-validated mouse model to test phenotypic effect of patient-derived mutations. It remains unclear whether specific targets of ZNF423 activity might be able to modulate phenotype. Aim 3 will determine whether decreasing activity of newly identified ZNF423-repressed genes, whose expression is increased in both knockdown cell and mutant animals, can improve cilium-dependent functions and emergent phenotypes in the Zfp423 mouse model.

项目总结: