Modeling the Structural and Mechanical Properties of Tissue During Zebrafish Tailbud Elongation

模拟斑马鱼尾芽伸长过程中组织的结构和力学特性

• 批准号: 2102789
• 负责人: Corey O'Hern
• 金额: $ 77.2万
• 依托单位: Yale University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2102789&HistoricalAwards=false
• 关键词: Modeling; Structural; Mechanical; Properties; Tissue

Cells need to move collectively in nearly all biological processes at the tissue scale. One of the most significant challenges to understanding collective cell motion is determining how single-cell motility strategies affect collective cell behavior at the tissue level. For example, do cells actively sense the direction of motion of their neighbors, or do cells primarily rely on cell-cell adhesion and repulsion from their neighbors to move collectively? To understand the mapping from single-cell properties to collective migration, the PI proposes a combined experimental and computational approach to investigate collective cell migration during convergent extension processes in the developing zebrafish spinal column. Using confocal microscopy and genetic variants, the PI will measure how alterations to cell-cell adhesion and planar cell polarity alter the flow of cells in three dimensions. He will then simulate convergent extension processes in the developing zebrafish spinal column using the deformable particle (DP) model in two and three spatial dimensions in realistic boundary conditions that are both deformable and contractile. The DP model also makes it possible to systematically vary the cell shape, cell-cell adhesion, and single-cell motility strategy. The PI will compare the results of the simulations to those obtained from 3D imaging of cell motion and shape of both wildtype and mutant zebrafish embryos. The proposed work will provide two significant advances to our understanding of collective cell motion: (1) how can we map single-cell properties to features of collective cell migration, and (2) what is a sufficient degree of model complexity to capture important features of collective cell migration? Currently, models for collective cell migration do not model true cell deformability and realistic cell motility strategies, but they can qualitatively capture several aspects of collective cell migration. These proposed simulations of deformable particles in both two and three dimensions, along with three-dimensional imaging of live tissue, will allow the team to determine what model ingredients are required to quantitatively describe collective cell migration. This project also includes a number of education and outreach activities that leverage the PIs' involvement in the Integrated Graduate Program in Physical and Engineering Biology. Initiatives will include mentoring high school and undergraduate students in research, developing a course module on computational modeling of cell migration during zebrafish spinal column development, and hosting short courses aimed at improving the presentation of scientific topics to non-scientific audiences by graduate students.The PI proposes coordinated experimental and computational studies to understand the role of cell shape change, motility strategy, and adhesion on collective cell motion during the convergent extension process in the elongating tail bud of zebrafish embryos. The PI will develop novel deformable particle (DP) model simulations in dynamic, deformable boundaries in both two and three spatial dimensions, which can quantitatively describe cell- and tissue-level deformation of developing zebrafish embryos and predict the effect of changes to single-cell biophysical parameters on collective cell motion. Complementary experiments will be performed on zebrafish embryos with varied cell motility and cell-cell adhesion through mutations to the planar cell polarity pathway and cadherin-mediated adhesion that enable the predictions of the DP model to be tested experimentally.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.

细胞需要在组织尺度上的几乎所有生物过程中集体移动。理解集体细胞运动的最大挑战之一是确定单细胞运动策略如何影响组织水平上的集体细胞行为。例如，细胞是主动感知相邻细胞的运动方向，还是主要依靠细胞间的粘附和来自相邻细胞的排斥来集体运动？为了了解从单细胞特性到集体迁移的映射，PI提出了一种结合实验和计算的方法来研究斑马鱼脊柱发育中会聚延伸过程中的集体细胞迁移。使用共聚焦显微镜和遗传变异，PI将测量细胞-细胞粘附和平面细胞极性的改变如何在三维中改变细胞的流动。然后，他将使用可变形粒子（DP）模型在二维和三维空间中模拟发育中的斑马鱼脊柱的收敛扩展过程，这些模型在现实的边界条件下既可变形又可收缩。DP模型还使得系统地改变细胞形状、细胞-细胞粘附和单细胞运动策略成为可能。PI将把模拟结果与野生型和突变型斑马鱼胚胎的细胞运动和形状的3D成像结果进行比较。这项工作将为我们理解集体细胞运动提供两个重要的进展：（1）我们如何将单细胞特性映射到集体细胞迁移的特征，以及（2）什么是足够的模型复杂度来捕获集体细胞迁移的重要特征？目前，集体细胞迁移的模型不模拟真实的细胞变形性和现实的细胞运动策略，但它们可以定性地捕捉集体细胞迁移的几个方面。这些提出的二维和三维可变形颗粒的模拟，沿着活组织的三维成像，将使研究小组能够确定定量描述集体细胞迁移所需的模型成分。该项目还包括一些教育和推广活动，利用PI参与物理和工程生物学综合研究生课程。计划将包括指导高中和本科生的研究，开发一个关于斑马鱼脊柱发育过程中细胞迁移的计算建模的课程模块，并举办短期课程，旨在改善研究生向非科学观众介绍科学主题。PI提出协调的实验和计算研究，以了解细胞形状变化，运动策略，和粘着作用对斑马鱼胚胎尾芽伸长过程中会聚延伸过程中细胞集体运动的影响。PI将在二维和三维空间的动态可变形边界中开发新型可变形粒子（DP）模型模拟，该模型可以定量描述发育中斑马鱼胚胎的细胞和组织水平变形，并预测单细胞生物物理参数变化对集体细胞运动的影响。补充实验将在斑马鱼胚胎上进行，这些胚胎具有不同的细胞运动性和细胞间粘附性，通过突变到平面细胞极性途径和钙粘蛋白介导的粘附，使DP模型的预测能够通过实验进行测试。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。