A human iPSC-based model of craniofrontonasal syndrome

项目总结 颅面畸形是人类常见的先天缺陷，对生活质量有重大影响。 受影响的个人。到目前为止，我们对这些先天畸形的大部分了解都依赖于 在老鼠模型上，这虽然是无价的，但在理解人类疾病方面有局限性。 人诱导多能干细胞(HiPSCs)为研究hPSCs提供了一个良好的平台。 与疾病相关的细胞类型中患者特定突变的后果。颅额鼻综合征(CFNS) 是一种X连锁疾病，会导致马赛克氏病患者出现戏剧性的头面部畸形 EFNB1基因突变。我们对小鼠模型的初步研究，结合已发表的工作， 表明ewitin-B1基于一种称为细胞的细胞现象重新组织头面部组织 分类。Eph/eaffin介导的细胞分选在多种发育系统中是常见的，但细胞和 发挥作用的分子机制还不完全清楚。我们已经建立了针对患者的HiPSCs 来自受CFNS影响的家庭中的多个人，并开发出与发育相关的人类 了解这种先天性头面部疾病的细胞模型系统。我们将确定基本的 细胞分选发生的细胞机制和决定Eph/EPhin介导的信号是如何 在CFNS患者来源的细胞类型中进行调节。

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.