Molecular and Cellular Control of Collective Cell Migration.

集体细胞迁移的分子和细胞控制。

基本信息

批准号：
10357669
负责人：
Holger Knaut
金额：
$ 46.46万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2024-01-31
项目状态：
已结题

项目摘要

ABSTRACT During embryonic development, cells often move in groups to assemble into tissues and organs. They are guided by attractant gradients and coordinate their migration to move in a directed manner. How attractant gradients are maintained and how cells in migrating groups coordinate their movements is unclear. To address these questions, we use the posterior lateral line primordium migration in zebrafish as a model. The primordium is a group of about 100 cells, which express the chemokine receptor Cxcr4 and follow a trail of Sdf1 chemokine. We have used this system to show that the primordium generates an Sdf1 gradient across itself by sequestering Sdf1 in its rear through the alternate Sdf1 receptor Cxcr7, a chemokine scavenger receptor. In Aim 1, we will determine how Sdf1 levels are controlled by the chemokine clearance receptor Cxcr7 using an Sdf1 signaling sensor that we developed. The cells in the primordium also express cadherins and adhere to each other tightly. In Aim 2, we will analyze the role of cadherins in coordinating collective migration and use cadherin-based tension sensors to measure the tension forces between the cells in the primordium. Our approach combines the optical accessibility of the zebrafish primordium with quantitative imaging, embryonic and genetic manipulations, and novel sensors for chemokine signaling and tension forces to provide a quantitative understanding of the molecular and cellular mechanisms underlying collective cell migration. We anticipate that our proposed studies will have two broad impacts on the field of cell migration. First, they will provide a quantitative understanding of how attractant gradients are regulated. Second, they will unravel the mechanics of cell-cell adhesion in a migrating tissue. These insights are key to understanding major biological and medical problems including defects in embryogenesis, organogenesis, and cancer metastasis.

抽象的在胚胎发育过程中，细胞经常分组以组装到组织和器官。他们以吸引力梯度为指导并协调其迁移以移动以定向方式。如何维持吸引力梯度以及迁移的细胞如何小组协调其运动尚不清楚。为了解决这些问题，我们使用后侧线原始迁移斑马鱼作为模型。原始物是一组约100个细胞，表达趋化因子受体CXCR4并沿SDF1趋化因子踪迹。我们已经使用了系统以表明原始物质会在自身中生成SDF1梯度通过替代SDF1受体CXCR7（趋化因子）在其后部隔离SDF1 清道夫受体。在AIM 1中，我们将确定SDF1级别如何由使用我们开发的SDF1信号传感器的趋化因子清除受体CXCR7。原始细胞还表达钙粘蛋白并彼此紧密粘附。在 AIM 2，我们将分析钙粘蛋白在协调集体迁移和使用中的作用基于钙粘蛋白的张力传感器，以测量细胞之间的张力原始。我们的方法结合了斑马鱼原始的光学可及性具有定量成像，胚胎和遗传操作以及新的传感器趋化因子信号传导和张力，以提供定量理解集体细胞迁移的基础分子和细胞机制。我们期待我们提出的研究将对细胞迁移领域产生两种广泛的影响。第一的，他们将对吸引力梯度的调节方式提供定量的理解。其次，它们将在迁移的组织中揭示细胞细胞粘附的力学。这些见解是理解主要的生物学和医学问题的关键胚胎发生，器官发生和癌症转移的缺陷。