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.

抽象的该研究项目整合了生物学、物理学和应用数学的概念，以产生将细胞力的产生和传递与迁移联系起来的新理解。主要关注领域是集体细胞迁移，它是组织发育和进展的重要过程的基础的疾病。该研究计划的长期愿景是应用基于实验的计算模型来预测生化扰动将如何影响集体迁移。这样的模型将能够设计控制集体迁移的方法，这将导致具有重要意义的治疗方法对人类健康的影响，例如慢性伤口的愈合、减缓癌细胞的侵袭，以及将组织工程化为所需的尺寸和形状。实现这种建模能力需要生物物理方法，因为运动是由细胞响应生物信号而产生的物理力，并通过细胞传递细胞层。尽管存在测量力的方法，但常用的方法通常是对于基于物理的集体运动模型或生化信号研究而言，信息不丰富产生力量。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底层生物学。这个为期 5 年的 MIRA 奖的目标是推进量化细胞力的方法体外和体内系统，并应用这些方法来构建能够建模的框架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，该研究将采取两种并行的方法。一种方法将会改进根据目前可用的实验方法来测量每个细胞产生的力，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方法与物理学相结合来量化细胞力。重要的是，这个新该方法将能够仅从细胞图像推断细胞力，这意味着它可以应用于复杂的细胞培养系统，甚至在体内。这两种方法将用于研究集体围绕两个互补的框架组织研究：第一个框架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进行运动；这第二个将确定多细胞群体之间的运动如何协调。这两个人在一起框架将提供一种手段，将关于集体移徙的观察结果组织成一个整体理解，这将暗示潜在的生物机制并提供重要的一步朝着实现基于实验的计算模型的目标迈进，该模型可以预测集体伤口愈合、癌症侵袭和组织工程等应用中的迁移。