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获取和组织的生物学和物理学原理。发育中的器官通常始于简单的组织，这些组织通常是扁平的，只包含几种细胞类型。然后组织会“自我组织”，这意味着它在没有更多外部输入的情况下会产生新的形状和细胞命运。理解从最初平坦的薄片中产生复杂的3D形状组织仍然是生物学中的一大挑战。这一过程是由细胞的分子和机械属性的变化驱动的，这些属性塑造了组织的形式和功能。这个过程是迭代的；例如，随着不同血统的细胞之间形成新的接触，又会发生几轮组织。因此，理解形态发生处于物理学和生物学的交界处，因为它涉及跨越多个时空尺度反馈的力学和基因表达的循环变化。有机化合物最近已成为研究人体器官发育的有力工具。尽管在一系列有机化合物方面取得了重大进展，特别是在复制体内细胞命运的决策方面，但塑造器官的生物物理过程仍然缺乏特征。在这个项目中，瑞安将利用神经元；这个系统复制了早期人类神经系统的发育。瑞安将在华威大学培养神经细胞。他将使用最先进的荧光成像工具：配备了用于深层组织成像的物镜的旋转圆盘显微镜；以及双光子显微镜。此外，Ryan将建立一个图像分析管道来提取神经样细胞形态发生过程中的3D细胞形状、细胞跟踪和命运。使用这个定量框架，我们将解决：1.细胞在形态发生过程中如何迁移，以及细胞命运如何反馈给细胞运动；2.对培养大小的限制如何影响细胞动力学和由此产生的器官形状；3.底层几何结构(例如，圆形或三角形区域上的细胞)的不对称是否会改变器官形态发生，如果是，是如何改变的？这个项目结合了有机体和成像的最新技术，以解决与MRC相关的一个主要问题：复杂器官形状是如何出现的？这些信息对于理解成人因发育缺陷而产生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.