Squeezing through the embryo:Dissecting nuclear mechanics during embryonic cell migration

挤压胚胎：剖析胚胎细胞迁移过程中的核力学

• 批准号: BB/W017482/1
• 负责人: Aparna Ratheesh
• 金额: $ 55.02万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW017482%2F1
• 关键词: Squeezing; through; embryo; Dissecting; nuclear

Macrophages are highly motile immune cells which often act as the first line of defence against pathogens. They also assist in wound healing and clearing up of dead cells and debris and tissue remodelling. All these functions are extremely important to ensure accurate animal development and homeostasis in the adult. They can also be reprogrammed to act in highly detrimental ways, assisting cancer metastasis and exacerbating inflammation. Since their ability to migrate underpins their ability to function accurately, understanding macrophage migration has important implications to our ability to ensure healthy living across the lifespan. We use the macrophages of the common fruit fly Drosophila Melanogaster as a model system to study macrophage migration. Fruit fly macrophages, also called haemocytes, are very like their vertebrate counterparts; they display similar origins and utilize similar mechanisms to migrate. Our recent work using the fruit fly macrophages in the embryo showed that they can squeeze into very dense tissue environments and this ability to migrate under tight confinement is important to ensure macrophage distribution within the embryo. In this proposal, we address the mechanisms through which the macrophage nucleus is moved through tissue barriers. The nucleus which is the repository of the genetic information also happens to be the stiffest organelle in the cell. Hence, moving the nucleus through barriers is not an easy task and nuclear deformation is key to migration under confinement. We have recently discovered that the macrophage nucleus undergoes extensive rearrangements in shape while they move through the embryo. Using a combination of biophysical and genetic experiments as well as cutting edge image analysis and mathematical modelling, we seek to understand the mechanical forces which are generated and transduced to deform and move the nucleus. We also seek to understand how nuclear deformations can in turn affect gene expression and thus macrophage functionality. We anticipate that fundamental principles which govern nuclear mechanics will be conserved across multiple cell types and the results of our proposal will inform studies not only on macrophage migration, but that of other embryonically migrating cell types and even metastatic cancer cells.

巨噬细胞是高度能动的免疫细胞，通常作为抵抗病原体的第一道防线。它们还有助于伤口愈合和清除死细胞和碎片以及组织重塑。所有这些功能对于确保成年动物的准确发育和体内平衡都是极其重要的。它们也可以被重新编程，以高度有害的方式发挥作用，帮助癌症转移和加剧炎症。由于它们的迁移能力是它们准确发挥功能的基础，因此了解巨噬细胞迁移对我们确保整个生命周期健康生活的能力具有重要意义。我们使用果蝇的巨噬细胞作为模型系统来研究巨噬细胞的迁移。果蝇巨噬细胞，也称为血细胞，非常像它们的脊椎动物对应物;它们显示出相似的起源并利用相似的机制进行迁移。我们最近在胚胎中使用果蝇巨噬细胞的工作表明，它们可以挤进非常密集的组织环境中，这种在严格限制下迁移的能力对于确保巨噬细胞在胚胎中的分布非常重要。在这个提议中，我们解决了巨噬细胞核通过组织屏障移动的机制。细胞核是遗传信息的储存库，也恰好是细胞中最坚硬的细胞器。因此，移动原子核通过势垒并不是一件容易的事情，原子核变形是限制下迁移的关键。我们最近发现，巨噬细胞核在胚胎中移动时会经历广泛的形状重排。使用生物物理和遗传实验以及尖端图像分析和数学建模的组合，我们试图了解产生和转换以变形和移动细胞核的机械力。我们还试图了解核变形如何反过来影响基因表达，从而影响巨噬细胞的功能。我们预计，控制核力学的基本原则将在多种细胞类型中得到保护，我们的提案的结果不仅将为巨噬细胞迁移的研究提供信息，而且还将为其他胚胎迁移细胞类型甚至转移性癌细胞的研究提供信息。