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Revealing forces driving collective cell migration

揭示驱动集体细胞迁移的力量

基本信息

批准号：
10711686
负责人：
Jacob K Notbohm
金额：
$ 38.21万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-19 至 2028-05-31
项目状态：
未结题

项目摘要

ABSTRACT This research program integrates concepts of biology, physics, and applied mathematics to produce new understanding connecting cell force generation and transmission to migration. A major area of focus is collective cell migration, which underlies essential processes in development of tissues and progression of disease. The long-term vision of this research program is to apply experiment-informed computational models to predict how biochemical perturbations will affect the collective migration. Such models would enable design of methods to control the collective migration, which would lead to therapies with important impacts on human health, such as healing of chronic wounds, slowing invasion of cancer cells, and engineering tissues of desired size and shape. Achieving this modeling capability requires a biophysical approach, because the motion results from physical forces that are produced by the cells in response to biological signaling and transmitted across the cell layer. Although there exist methods to measure the forces, the common methods used are often uninformative for physics-based models of collective motion or for studies of the biochemical signaling that produces the forces. Thus, there is a need to improve upon current methods and to develop new methods to quantify forces while simultaneously connecting to both the physics-based models and the underlying biology. The goals for this 5-year MIRA award are to advance methods in quantifying cell forces in both in vitro and in vivo systems and to apply those methods to build frameworks that enable modeling the relationships between biochemical signaling, forces, and motion in collective cell migration. To accomplish these goals, the research will take two parallel approaches. One approach will improve upon currently available experimental methods to measure forces produced by each cell, including the variation of those forces in space and time. The other approach will develop a new methodology for quantifying cell forces by integrating methods of data science with physics. Importantly, this new methodology will be able to infer cell forces from only images of the cells, meaning it can be applied in complicated cell culture systems and even in vivo. The two approaches will be used to study the collective migration by organizing the research around two complementary frameworks: the first will study collective motion by focusing on the forces associated with local rearrangements between neighboring cells; the second will determine how motion is coordinated across multicellular groups. Together, these two frameworks will provide a means to organize observations about collective migration into a holistic understanding, which will hint at the underlying biological mechanisms and provide an essential step forward towards achieving experiment-informed computational models that can predict the collective migration in applications such as wound healing, cancer invasion, and tissue engineering.

摘要该研究计划整合了生物学，物理学和应用数学的概念，新的理解连接细胞力的产生和传输迁移。一个主要的重点领域是集体细胞迁移，这是组织发育和进展的基本过程的基础疾病。这项研究计划的长期愿景是将实验信息化的计算模型来预测生物化学扰动将如何影响集体迁移。这些模型将能够设计控制集体迁移的方法，这将导致重要的治疗方法，对人体健康的影响，如慢性伤口的愈合，减缓癌细胞的侵袭，将组织改造成所需的大小和形状。实现这种建模能力需要一种生物物理方法，因为运动的结果来自于细胞响应生物信号产生的物理力，细胞层。虽然存在测量力的方法，但常用的方法通常是对于集体运动的基于物理学的模型或对于产生力量。因此，需要改进现有方法并开发新方法量化力，同时连接到基于物理的模型和基础生物学这个为期5年的MIRA奖项的目标是推进量化细胞力量的方法，体外和体内系统，并应用这些方法来建立框架，使建模的在集体细胞迁移中生化信号、力和运动之间的关系。为了实现这些目标，研究将采取两种并行的方法。一种方法将改善基于目前可用的实验方法来测量由每个细胞产生的力，包括这些力在空间和时间上的变化。另一种方法将开发一种新的方法，通过将数据科学与物理学相结合的方法来量化细胞力。重要的是，这个新一种方法将能够仅从细胞的图像推断细胞力，这意味着它可以应用于复杂的细胞培养系统，甚至在体内。这两种方法将被用来研究集体通过围绕两个互补的框架组织研究：第一个将研究集体通过关注与相邻细胞之间的局部重排相关的力来实现运动; 第二个将决定多细胞群体之间的运动如何协调。这两个人一起框架将提供一种手段，将关于集体移徙的观察组织成一个整体，理解，这将暗示潜在的生物机制，并提供一个重要的步骤，朝着实现实验知情的计算模型，可以预测集体在诸如伤口愈合、癌症侵袭和组织工程的应用中的迁移。