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A human iPSC-based model of craniofrontonasal syndrome

基于人类 iPSC 的颅额鼻综合征模型

基本信息

批准号：
9242856
负责人：
Jeffrey Ohmann Bush
金额：
$ 19.81万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9242856
关键词：
Adhesions Affect Attenuated Behavior Binding Biological Biological Assay Biological Models Biology Biophysics Birth CRISPR interference Cell Adhesion Cell Line Cell Separation Cell model Cells Characteristics Childhood Congenital Abnormality Craniofacial Abnormalities Data Development Disease Emigrations Eph Family Receptors Ephrin B Receptor Ephrin-B1 Ephrins Etiology Exhibits Family Female Functional disorder Generations Genes Genetic Heterozygote Human Individual Inheritance Patterns Link Measures Mediating Modeling Molecular Mosaicism Mus Mutation Neural Crest Cell Neuroepithelial Cells Neurologic Outcome Pathogenesis Patients Play Prediabetes syndrome Property Proteins Publishing Quality of life Receptor Activation Receptor Signaling Regulation Severities Signal Transduction Study models Surgeon System Technology Testing Tissues Work X Inactivation axon guidance base cell behavior cell type clinical application congenital anomaly craniofacial craniofacial development craniofrontonasal syndrome disease mechanisms study genome editing human disease induced pluripotent stem cell insight live cell imaging loss of function mutation male malformation member mouse model mutant neuroepithelium novel overexpression response segregation skeletal

项目摘要

Project summary Craniofacial anomalies are common human birth defects that have dramatic impact on the quality of life of the affected individual. To date, the bulk of our understanding of these congenital anomalies has depended on mouse models, which, though invaluable, have limitations in their use in understanding human diseases. Human induced pluripotent stem cells (hiPSCs) provide a promising platform for the study of the consequences of patient-specific mutations in disease-relevant cell types. Craniofrontonasal syndrome (CFNS) is an X-linked disease that causes dramatic craniofacial dysmorphogenesis in patients that are mosaic for mutations in the EFNB1 gene. Our preliminary studies in mouse models, in combination with published work, indicate that ephrin-B1 acts to re-organize craniofacial tissues based on a cellular phenomenon known as cell sorting. Eph/ephrin-mediated cell sorting is common to multiple developmental systems, but the cellular and molecular mechanisms at play are incompletely understood. We have established patient-specific hiPSCs from multiple individuals in a family affected by CFNS and have developed a developmentally relevant human cellular model system for understanding this congenital craniofacial disease. We will determine the basic cellular mechanisms by which cell sorting occurs and determine how Eph/Ephrin-mediated signaling is regulated in CFNS patient-derived cell types.

项目总结