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.

细胞几乎需要在组织尺度上几乎所有生物过程中集体移动。理解集体细胞运动的最重要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，细胞会积极地感知其邻居的运动方向，还是主要依赖细胞 - 细胞粘附和邻居的抑制来集体运动？为了了解从单细胞性质到集体迁移的映射，PI提出了一种合并的实验和计算方法，以研究在发育中的斑马鱼脊柱中收敛扩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将测量细胞细胞粘附的改变和平面细胞极性如何改变三维细胞的流动。然后，他将使用可变形粒子（DP）模型在两个和三个空间维度中使用可变形和收缩的两个空间维度中的可变形粒子（DP）模型模拟​​斑马鱼脊柱中的收敛扩展过程。 DP模型还可以系统地改变细胞形状，细胞 - 细胞粘附和单细胞运动策略。 PI将将模拟的结果与从野生型和突变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。提出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）什么是足够的模型复杂性来捕获集体细胞迁移的重要特征？当前，集体细胞迁移的模型不能模拟真实的细胞变形性和逼真的细胞运动策略，但它们可以定性地捕获集体细胞迁移的几个方面。这些提出的对两个和三维中可变形颗粒的模拟，以及对活组织的三维成像，将使团队能够确定需要哪些模型成分来定量描述集体细胞迁移。该项目还包括许多教育和外展活动，这些活动利用了PIS参与物理和工程生物学综合研究生计划。倡议将包括指导高中和本科生研究，开发一个课程模块，以对斑马鱼脊柱开发期间的细胞迁移进行计算模型，并托管旨在改善科学主题向非科学受众介绍的简短课程。斑马鱼胚胎的拉长尾芽中的延伸过程。 PI将在两个和三个空间尺寸的动态，可变形边界中开发新颖的可变形粒子（DP）模型模拟​​，这些粒子可以定量描述斑马鱼胚胎的细胞和组织水平变形，并预测单细胞生物物质参数对集体细胞运动的变化的影响。通过对平面细胞极性途径和钙粘蛋白介导的粘附的突变，将对具有不同细胞运动性和细胞细胞粘附的斑马鱼胚胎进行互补实验，从而使DP模型的预测能够在实验上进行测试，这反映了NSF的法定任务和依据的依据。