Signaling control and cellular basis of craniofacial morphogenesis and congenital disease

颅面形态发生和先天性疾病的信号控制和细胞基础

• 批准号: 10447898
• 负责人: Jeffrey Ohmann Bush
• 金额: $ 106.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2030-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10447898
• 关键词: Address; Automobile Driving; Behavior; CRISPR/Cas technology; Cell Separation; Cell physiology; Cells; Choristoma; Collaborations; Congenital Abnormality; Craniofacial Abnormalities; Disease; Dysmorphology; Embryo; Epithelial; Goals; Human; Knowledge; Laboratories; Lead; Lip structure; Mesenchymal; Methodology; Modeling; Molecular; Morphogenesis; Mus; Mutagenesis; Operative Surgical Procedures; Pattern; Process; Resolution; Secondary Palate; Series; Shapes; Signal Transduction; System; Techniques; Therapeutic; Time; Tissue Engineering; Tissues; cell behavior; cell motility; congenital anomaly; craniofacial; craniofacial development; craniofacial structure; craniofacial tissue; craniofrontonasal syndrome; gene regulatory network; imaging platform; novel; novel strategies; physical process; tool

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.

项目摘要 先天性颅面异常是常见的，是由导致异常组织水平的细胞变化引起的 形状的改变。尽管对模式颅面的基因调节网络的深入了解 已经实现了有关驱动颅面的细胞和物理过程的知识 形态发生滞后。在细胞变化上存在特定信息的特定信息，以驱动特定的信息 颅面畸形。近年来，我的实验室组装了一系列工具并建立了 一个协作网络，以解决形态发生物理方面的信号控制。通过生成 用于研究唇彩和次级味融合的新的实时成像平台，我们已经确定了新型的细胞 有助于这一过程的行为。我们对细胞机制进行了详细的了解 颅面综合征，我们已经从异常细胞隔离行为中学到了结果 并导致组织形状的变化。我们已经建立了颅面状况的第一个HIPSC模型， 允许我们第一次解决人类系统中细胞形态发生的问题。我们在这里提出 一系列的新方向集中于颅面形态发生的细胞基础以及如何出现问题 在先天性颅面状况下。其中包括三个主要目标：1）了解间充质的控制 颅面组织的细胞运动2）阐明颅面上皮组织融合的机制 细胞和分子分辨率3）哺乳动物颅面形态发生的精心制作的新型调节剂 人类颅面疾病偏见的诱变方法中的尖端CRISPR/CAS9方法论。 实现这些目标将推动颅面中细胞形态发生的基本原理的理解 开发并越来越提供机会使这些原则适应治疗和组织 治疗先天性颅面异常的工程方法。