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: 10599976
• 负责人: Jeffrey Ohmann Bush
• 金额: $ 104.19万
• 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/10599976
• 关键词: Address; Automobile Driving; Behavior; CRISPR/Cas technology; Cell Separation; Cell physiology; Cells; Choristoma; Collaborations; Congenital Abnormality; Craniofacial Abnormalities; Disease; Dysmorphology; Embryo; Epithelium; Goals; Human; Knowledge; Laboratories; Learning; 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 先天性颅面畸形是常见的，由细胞变化引起的异常组织水平引起。 形状上的变化。尽管对颅面部模式的基因调控网络有重要的理解 已经取得了发展，关于驱动颅面的细胞和物理过程的知识 形态发生滞后。关于驱动特定的细胞变化的信息特别匮乏 头面部畸形。近年来，我的实验室组装了一系列工具，并建立了 一个合作网络，解决形态发生的物理方面的信号控制。通过生成 用于唇腭裂融合研究的新的活体成像平台，我们发现了新的细胞 促成这一过程的行为。我们一直在寻求对细胞机制的详细了解 颅额鼻综合征，我们已经了解到这种情况是由于异常的细胞分离行为造成的 以及由此产生的组织形状的变化。我们已经建立了第一个头面部疾病的HiPSC模型， 这使得我们第一次能够解决人类系统中细胞形态发生的问题。在这里，我们建议 关注颅面形态发生的细胞基础以及它是如何出错的一系列新方向 在先天颅面条件下。这些包括三个主要目标：1)了解间充质细胞的控制 头面部组织成形过程中的细胞运动2)阐明头面部上皮组织融合的机制 细胞和分子分辨率3)阐述了哺乳动物头面部形态发生的新调节因子 在人类颅面部疾病偏向突变方法中的尖端CRISPR/CAS9方法学。 实现这些目标将推动对颅面细胞形态发生的基本原理的理解 发展，并越来越多地提供机会，使这些原则适用于治疗和组织 治疗先天性颅面畸形的工程学方法。