A human iPSC-based model of craniofrontonasal syndrome

项目摘要 颅面畸形是人类常见的出生缺陷，对生活质量有着巨大的影响 受影响的个人。到目前为止，我们对这些先天性异常的大部分理解都依赖于 尽管小鼠模型非常宝贵，但在理解人类疾病方面存在局限性。 人诱导多能干细胞（hiPSC）为研究造血干细胞的分化提供了一个有希望的平台。 疾病相关细胞类型中患者特异性突变的后果。颅额鼻综合征 是一种X连锁疾病，可导致患者出现严重的颅面畸形， EFNB1基因突变。我们在小鼠模型中的初步研究，结合已发表的工作， 表明肝配蛋白-B1基于称为细胞细胞现象来重组颅面组织 分类Eph/肝配蛋白介导的细胞分选在多种发育系统中是常见的，但细胞和 起作用的分子机制还不完全清楚。我们已经建立了患者特异性hiPSCs 来自受CFNS影响的家庭中的多个个体，并且已经发展出发育相关的人类 细胞模型系统来了解这种先天性颅面疾病。我们将确定基本的 细胞分选发生的细胞机制，并确定Eph/Ephrin介导的信号传导如何 在CFNS患者来源的细胞类型中调节。

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.