Polarity signaling within and between cells analyzed in a 1D model of collective cell migration

在集体细胞迁移的一维模型中分析细胞内和细胞间的极性信号传导

基本信息

批准号：
RGPIN-2018-05831
负责人：
Hayer, Arnold
金额：
$ 2.26万
依托单位：
McGill University
依托单位国家：
加拿大
项目类别：
Discovery Grants Program - Individual
财政年份：
2019
资助国家：
加拿大
起止时间：
2019-01-01 至 2020-12-31
项目状态：
已结题

来源：
https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684022
关键词：
Polarity signaling within between cells

项目摘要

Animal tissues are composed of large numbers of cells that together determine tissue shape and function. Collective behavior of cells in tissues is only possible when individual cells coordinate their behavior with their neighbors, by integrating signals that they receive from them or from their environment. During collective cell migration, individual cells employ their autonomous migration machinery for locomotion, while they are coupled to their neighbors through adhesive cell-cell contacts. Collective cell guidance therefore requires that adjacent cells coordinate their motility and polarity systems through intercellular communication. Despite the known importance of collective cell migration during development, tissue repair, and disease, fundamental aspects of how collective cell guidance is achieved remain unclear. A detailed understanding of the mechanisms mediating intercellular communication requires quantitative measurements of relevant structural and signaling parameters both in autonomously and collectively migrating cells. In this discovery research program, we will follow a novel strategy at the interface between biology, engineering, and physics, combining fluorescence-based biosensor measurements in live cells with microfabrication and computational image analyses. Micropatterned substrates with defined geometries will force otherwise heterogeneously behaving cells into predicable migration behaviors. Spatiotemporal patterns of multiple biosensor signals recorded individually can then be aligned to precise behavioral landmarks and their relationship to each other determined. ******In Aim 1, we will study autonomous signaling in individually migrating cells. We will spatiotemporally map patterns of signaling activities in unpolarized cells, in cells migrating on linear tracks, and during defined migration events, e.g. turning or repolarization. ******In Aim 2, we will use a simplified model of collective cell migration, where cells migrate collectively as trains on linear or circular micropatterned tracks. We will investigate how interactions between cells inform and modify autonomous signaling activities to achieve collective migration. ******This research program will establish relationships between critical signaling components and morphological changes, and create a new level of understanding of the complex mechanisms that govern autonomous and collective cell migration. By investigating how the signaling activities required for autonomous and collective cell migration are regulated in time and space, we aim to identify mechanisms of intercellular communication mediating collective cell behavior. Moreover, the proposed research will provide an excellent training opportunity for trainees interested in using cutting-edge technology that links physical approaches to studying fundamental aspects of collective cell behavior.

动物组织由大量细胞组成，这些细胞共同决定组织形状和功能。仅当单个细胞与邻居的行为协调，通过整合从他们或环境中收到的信号来协调其行为时，细胞在组织中的集体行为才有可能。在集体细胞迁移期间，各个细胞采用其自主迁移机制进行运动，而它们通过粘合性细胞细胞接触耦合到邻居。因此，集体细胞引导要求相邻的细胞通过细胞间通信协调其运动性和极性系统。尽管在发育，组织修复和疾病期间集体细胞迁移的重要性已知，但如何实现集体细胞指导的基本方面仍不清楚。对介导细胞间通信的机制的详细理解，需要对相关的结构和信号传导参数进行定量测量，包括自主和集体迁移的细胞。在此发现研究计划中，我们将遵循生物学，工程和物理学之间接口的新策略，将基于荧光的生物传感器测量与微观分析和计算图像分析相结合。具有定义的几何形状的微图案底物将迫使异质行为将细胞转变为可预测的迁移行为。然后可以单独记录的多个生物传感器信号的时空模式对齐，以确定精确的行为标志及其彼此之间的关系。 ******在AIM 1中，我们将研究单独迁移细胞中的自主信号传导。我们将在非极化细胞中，在线性轨道上迁移以及在定义的迁移事件中的细胞中的信号传导活性的空间绘制模式。转弯或复极化。 ******在AIM 2中，我们将使用一个简化的集体细胞迁移模型，其中细胞在线性或圆形微图案轨道上集体迁移。我们将调查细胞之间的相互作用如何通知并修改自主信号传导活动以实现集体迁移。 ******该研究计划将建立关键信号成分与形态变化之间的关系，并对控制自主和集体细胞迁移的复杂机制有了新的了解。通过调查自主和集体细胞迁移所需的信号传导活动在时间和空间中如何调节，我们旨在确定介导集体细胞行为的细胞间通信的机制。此外，拟议的研究将为有兴趣使用尖端技术的学员提供一个极好的培训机会，这些技术将物理方法与研究集体细胞行为的基本方面联系起来。