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Collective Gradient Sensing and Cell-to-Cell Variability - Theory and Experiment

集体梯度传感和细胞间变异性 - 理论与实验

基本信息

批准号：
1915491
负责人：
Brian Camley
金额：
$ 48万
依托单位：
Johns Hopkins University
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1915491&HistoricalAwards=false
关键词：
Collective Gradient Sensing Cell Variability

项目摘要

This project will help understand how cells can work together to interpret external signals and collectively make decisions. Earlier work from the Ewald group showed that cells in tissues cooperate to make decisions, such as choosing when and where to move. This cooperation can help make more reliable decisions. One example of this is that when many cells work together to follow a chemical signal, they are more precise and reliable than a single cell on its own. This project studies how this happens, and how cells can work together even when each cell can have highly variable responses to a signal – when cells are individually unreliable. This project has two critical types of experiments – both of which supplemented by computational modeling and mathematical theory. In the first experiment type, a highly variable collection of cells will be created, combined of cells that think they see a signal telling them to move or grow (active cells), and those that don’t (inactive cells). To understand how these cells work together to make decisions, mathematical models will be used to predict the final decision the cells make – the direction of tissue growth – from the initial location of the active cells. In the second experiment type, the cells will be exposed to an external signal. How precisely will branch locations follow this signal? Is this affected by cell variation (different fractions of active cells)? These experimental results and others will be described with computational models that include both the physical forces between cells and the motion of the molecules that the cells are sensing. Understanding how cells cooperate in this way will help us understand how developing embryos are reliably formed – when cells end up in the wrong place, this can lead to birth defects. This project will also support the training of students from the high school level to graduate students. High school students will be recruited from Baltimore schools through the Women in Science and Engineering (WISE) program to participate in research. In addition, students trained through this project will be trained in collaborative writing and outreach. Cells within tissues and organs cooperate in order to move and sense signals; this cooperation allows them to perform tasks that single cells cannot. A dramatic example, and the major focus of this project, is collective gradient sensing, where groups of cells measure a signal gradient, even when a single cell cannot. Collective gradient sensing involves comparisons between cells, and will be strongly affected by cell-to-cell variability, as even genetically identical cells can have highly variable motilities and responses to signal. Understanding collective gradient sensing will require quantifying these cell-to-cell variations and modeling their consequences. This project is a combined experiment and theory approach to understanding collective gradient sensing and cell-to-cell variation by 1) testing existing hypotheses in mammary organoids where variability can be induced, and 2) developing improved models that address variability in cell motility, cell cycle, and cell division. Collective gradient sensing accuracy should – in theory – depend on a balance of cell variability and the ability of a tissue to re-arrange. Variability and fluidity will be controlled and measured in experiments on branching mammary organoids, which undergo collective gradient sensing. Experiments on organoids will be performed to simultaneously characterize sensing and fluidity to test this idea. In addition, artificial variability will be induced by studying mosaic organoids. These experiments will be analyzed with simple stochastic models previously developed by the Camley group. Motivated by the results of these experiments, new computational models of organoids with cell-to-cell variation in signaling, mechanical, and motility properties will be created using both self-propelled particle and biochemical/mechanical cell models. Estimation theory will be used to find fundamental limits to accurate group decisions.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该项目将有助于了解细胞如何共同工作来解释外部信号并共同做出决定。Ewald小组的早期工作表明，组织中的细胞合作做出决定，例如选择何时何地移动。这种合作有助于做出更可靠的决策。其中一个例子是，当许多细胞一起工作以跟踪化学信号时，它们比单个细胞更精确和可靠。该项目研究了这是如何发生的，以及细胞如何在每个细胞对信号的反应高度可变的情况下协同工作-当细胞单独不可靠时。该项目有两种关键类型的实验-两者都辅以计算建模和数学理论。在第一种实验类型中，将创建一个高度可变的细胞集合，将认为它们看到了告诉它们移动或生长的信号的细胞（活跃细胞）和那些没有看到的细胞（不活跃细胞）结合起来。为了了解这些细胞如何共同做出决定，将使用数学模型来预测细胞从活性细胞的初始位置做出的最终决定-组织生长的方向。在第二种实验类型中，细胞将暴露于外部信号。分支位置将如何精确地遵循此信号？这是否受到细胞变异（不同活性细胞分数）的影响？这些实验结果和其他结果将通过计算模型进行描述，这些模型包括细胞之间的物理力和细胞所感测的分子运动。了解细胞如何以这种方式合作将有助于我们了解发育中的胚胎是如何可靠地形成的-当细胞最终出现在错误的位置时，这可能导致出生缺陷。该项目还将支持从高中到研究生的学生培训。高中生将通过科学和工程妇女（WISE）计划从巴尔的摩学校招募参加研究。此外，通过该项目培训的学生将接受合作写作和外联方面的培训。组织和器官内的细胞相互合作，以移动和感知信号;这种合作使它们能够执行单个细胞无法执行的任务。一个戏剧性的例子，也是这个项目的主要焦点，是集体梯度传感，其中细胞组测量信号梯度，即使单个细胞不能。集体梯度感测涉及细胞之间的比较，并且将受到细胞间变异性的强烈影响，因为即使是遗传上相同的细胞也可以具有高度可变的运动性和对信号的响应。理解集体梯度感知将需要量化这些细胞间的变化并对其后果进行建模。该项目是一种结合实验和理论的方法，通过1）测试可以诱导变异性的乳腺类器官中的现有假设，以及2）开发改进的模型，解决细胞运动，细胞周期和细胞分裂的变异性，来理解集体梯度传感和细胞间变异。理论上，集体梯度感测准确度应该取决于细胞可变性和组织重新排列的能力的平衡。变异性和流动性将在分支乳腺类器官的实验中进行控制和测量，这些器官经历集体梯度传感。将进行类器官实验，同时表征传感和流动性，以测试这一想法。此外，通过研究镶嵌类器官将诱导人工变异。这些实验将分析与简单的随机模型先前开发的Camley组。受这些实验结果的启发，将使用自推进颗粒和生化/机械细胞模型创建具有信号传导，机械和运动特性的细胞间变化的类器官的新计算模型。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。