Signaling control and cellular basis of craniofacial morphogenesis and congenital disease

项目摘要 先天性颅面畸形是常见的，由细胞变化引起的异常组织水平 形状的变化。尽管对颅面结构的基因调控网络有着深刻的理解， 发展已经实现，关于驱动颅面的细胞和物理过程的知识 形态发生滞后。一个特别缺乏的信息存在的细胞变化，驱动特定的 颅面畸形近年来，我的实验室组装了一系列工具， 一个合作网络，以解决形态发生的物理方面的信号控制。通过生成 新的实时成像平台的研究唇和继发性腭融合，我们已经确定了新的细胞 这些行为有助于这一过程。我们已经对细胞机制进行了详细的了解 颅额鼻综合征，我们已经了解到这种情况是由异常的细胞分离行为引起的 以及由此产生的组织形状的变化。我们已经建立了第一个颅面疾病的hiPSC模型， 让我们第一次在人类系统中解决细胞形态发生的问题。在这里我们建议 一系列新的方向，重点是颅面形态发生的细胞基础，以及它是如何出错的， 先天性颅面疾病这些包括三个主要目标：1）了解间充质的控制 2）阐明颅面上皮组织融合的机制， 细胞和分子分辨率3）通过使用来阐述哺乳动物颅面形态发生的新调节因子 最先进的CRISPR/Cas9方法在人类颅面疾病偏置诱变方法中的应用。 实现这些目标将推动对颅面神经细胞形态发生基本原理的理解。 发展和越来越多地提供机会，使这些原则适用于治疗和组织 工程方法来治疗先天性颅面畸形。

Project Summary Congenital craniofacial anomalies are common and arise from cellular changes that cause aberrant tissue-level alterations in shape. Though significant understanding of the gene regulatory networks that pattern craniofacial development has been achieved, knowledge regarding the cellular and physical processes driving craniofacial morphogenesis lags behind. A particular paucity of information exists on the cellular changes that drive specific craniofacial dysmorphologies. In recent years, my laboratory has assembled a battery of tools and established a network of collaborations to address the signaling control of physical aspects of morphogenesis. By generating new live imaging platforms for the study of lip and secondary palate fusion, we have identified novel cellular behaviors that contribute to this process. We have pursued a detailed understanding of the cellular mechanisms of craniofrontonasal syndrome, a condition that we have learned results from aberrant cell segregation behavior and resultant changes in tissue shape. We have established the first hiPSC model of a craniofacial condition, allowing us to address questions of cellular morphogenesis in a human system for the first time. Here we propose a series of new directions that focus on the cellular basis of craniofacial morphogenesis and how it goes wrong in congenital craniofacial conditions. These include three main goals: 1) Understand the control of mesenchymal cell movement in shaping craniofacial tissues 2) Elucidate mechanisms of craniofacial epithelial tissue fusion at cellular and molecular resolution 3) Elaborate novel regulators of mammalian craniofacial morphogenesis by use of cutting edge CRISPR/Cas9 methodology in a human craniofacial disease-biased mutagenesis approach. Achieving these goals will drive understanding of basic principles of cellular morphogenesis in craniofacial development and increasingly provide opportunities to adapt these principles toward therapeutic and tissue engineering approaches to treat congenital craniofacial anomalies.