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.

在组织规模的几乎所有生物过程中，细胞都需要集体移动。理解集体细胞运动的最重大挑战之一是确定单细胞运动策略如何影响组织水平的集体细胞行为。例如，细胞是否主动感知邻近细胞的运动方向，或者细胞是否主要依靠细胞与细胞的粘附和邻近细胞的排斥来集体移动？为了理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发育中的斑马鱼脊柱会聚伸展过程中的集体细胞迁移。使用共聚焦显微镜和遗传变异，PI 将测量细胞间粘附和平面细胞极性的改变如何改变细胞在三个维度上的流动。然后，他将在可变形和可收缩的现实边界条件下，使用二维和三维空间维度的可变形粒子 (DP) 模型来模拟发育中的斑马鱼脊柱的收敛伸展过程。 DP 模型还可以系统地改变细胞形状、细胞间粘附和单细胞运动策略。 PI 将把模拟结果与通过野生型和突变型斑马鱼胚胎的细胞运动和形状的 3D 成像获得的结果进行比较。拟议的工作将为我们对集体细胞运动的理解提供两个重大进展：（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）什么是足够程度的模型复杂性来捕获重要特征细胞集体迁移？目前，集体细胞迁移模型并未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获集体细胞迁移的几个方面。这些提出的二维和三维可变形粒子模拟以及活体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。该项目还包括一些利用 PI 参与物理和工程生物学综合研究生项目的教育和外展活动。举措将包括指导高中生和本科生进行研究，开发斑马鱼脊柱发育过程中细胞迁移计算模型的课程模块，以及举办旨在改善研究生向非科学受众展示科学主题的短期课程。 PI提出协调实验和计算研究，以了解斑马鱼胚胎尾芽伸长过程中细胞形状变化、运动策略和粘附对集体细胞运动的作用。 PI将在两个和三个空间维度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的斑马鱼胚胎的细胞和组织水平变形，并预测变化对单细胞的影响集体细胞运动的生物物理参数。将通过平面细胞极性途径和钙粘蛋白介导的粘附的突变，对具有不同细胞运动性和细胞间粘附的斑马鱼胚胎进行补充实验，从而使 DP 模型的预测能够得到实验检验。该奖项反映了 NSF 的法定使命和通过使用基金会的智力优点和更广泛的影响审查标准进行评估，该项目被认为值得支持。