Determining the role of boundary constraints and initial conditions on 4D cell morphodynamics during neural development.

该项目的目的是了解组织形状的获取和组织背后的生物和物理原理。发育中的器官通常从简单的组织开始，这些组织通常是扁平的，只包含几种细胞类型。然后组织“自我组织”，这意味着它产生新的形状和细胞命运，而不需要进一步的外部输入。理解从最初的平面组织生成复杂的3D形状组织仍然是生物学中的一个主要挑战。这个过程是由塑造组织形态和功能的细胞的分子和机械特性的变化所驱动的。这个过程是迭代的；例如，当不同谱系的细胞之间形成新的联系时，进一步的组织就会发生。因此，理解形态发生存在于物理学和生物学之间的界面，因为它涉及力学和基因表达的变化周期，这些变化周期在多个时空尺度上反馈。类器官最近成为研究人体器官发育的有力工具。尽管在一系列类器官方面取得了重大进展，特别是在体内复制细胞命运决策方面，但塑造器官的生物物理过程仍然缺乏特征。在这个项目中，Ryan将利用神经类；这个系统复制了早期人类神经系统的发育过程。瑞安会在沃里克培养神经细胞。他将使用最先进的荧光成像工具：配有深层组织成像物镜的旋转圆盘显微镜；还有双光子显微镜。此外，Ryan将建立一个图像分析管道来提取3D细胞形状、细胞跟踪和神经样形态发生过程中的命运。使用这个定量框架，我们将解决：1。1 .细胞在形态发生过程中如何迁移，细胞命运如何反馈到细胞运动中；2 .限制培养大小对细胞动力学和器官形状的影响；底层几何结构的不对称（如圆形或三角形区域的细胞）是否会改变器官的形态发生，如果是，是如何改变的？该项目汇集了类器官和成像方面的最新技术，以解决与MRC相关的一个主要问题：复杂的器官形状是如何出现的？这些信息对于了解成人由于发育过程中的缺陷而引起的疾病具有很高的针对性。

The aim of the project is to understand the biological and physical principles that underlie the acquisition and organisation of tissue shape.Developing organs typically start as simple tissues, which are often flat and contain only a few cell types. The tissue then "self-organises", meaning that it generates new shapes and cell fates without further external inputs. Understanding the generation of complex 3D shaped tissues from initially flat sheets remains a major challenge in biology. This process is driven by changes in the molecular and mechanical properties of the cells that shape the form and function of tissues. This process is iterative; e.g. as new contacts form between cells of different lineages, further rounds of organisation take place. Thus, understandingmorphogenesis lies at the interface between physics and biology as it involves cycles of changes in mechanics and gene expression that feedback across multiple spatiotemporal scales. Organoids have recently emerged as a powerful tool for investigating human organ development. Despite significant progress being made in a range of organoids, especially to replicate in vivo cell fate decision making, the biophysical processes that shape organs remain poorly characterised.In this project, Ryan will take advantage of neuruloids; this system replicates developmentof the early human nervous system. Ryan will culture neuruloids at Warwick. He will use state-of-the-art fluorescent imaging tools: spinning disc microscopy equipped with objectives for deep tissue imaging; and 2-photon microscopy. Further, Ryan will build an image analysis pipeline to extract 3D cell shape, cell tracking, and fate during neuruloid morphogenesis.Using this quantitative framework, we will address:1. how cells migrate during morphogenesis, and how cell fate feeds back into cellular motion;2. how constraints on culture size affect cell dynamics and the resulting organ shape;3. whether asymmetries in the underlying geometry (e.g. cells on either circular or triangular domains) alters organ morphogenesis, and if so, how?This project brings together the latest technologies in organoids and imaging to tackle a major question relevant to the MRC: how does complex organ shape emerge? Such information is highly pertinen to understanding diseases in adult which derive from defects during development.