3D Mechanical Modeling of Epithelial Stratification and Turnover

上皮分层和更新的 3D 机械建模

• 批准号: 2230841
• 负责人: Mary Lisa Manning
• 金额: $ 33.85万
• 依托单位: Syracuse University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2230841&HistoricalAwards=false
• 关键词: 3D; Mechanical; Modeling; Epithelial; Stratification

Skin is a biological tissue composed of multiple components and cell types which work in concert to perform critical functions, such as creating a flexible barrier to the outside environment and healing wounds. To perform these functions, skin has multiple layers – a bottom layer composed of cells that can divide and transform into other cell types, and top layers of cells that rarely divide and have specialized shapes with specific tasks. Recent research hints that mechanical interactions between these cell types help keep the layers separate and regulate cell divisions, but there are few quantitative models to carefully test this hypothesis. This project will develop a new biophysical computational model for skin layers that accounts for mechanical interactions between cells. In collaboration with cell biology experiments, this research will link model parameters to the expression of specific biomolecules, such as adhesion molecules or components of the cell cytoskeleton. It will then make predictions for cell and tissue shapes, as well as the rates at which cells leave the bottom layer to renew the tissue over time. These predictions will be tested in experiments. Finally, it will test the hypothesis that cells sense mechanical signals transmitted through the tissue and consequently alter the production of adhesion and cytoskeletal molecules, resulting in a mechanical feedback loop that helps to correctly regulate tissue growth and prevent disease. The researchers will provide a publicly available simulation code for 3D epithelial tissues, engage students under-represented in STEM fields in research and professional development experiences, and disseminate lectures and computational exercises on modeling cell mechanics.The goal of this project is to make and test quantitative predictions for the mechanical response of self-renewing stratified epithelia, using mammalian skin as a model system. The project will develop a novel 3D computational model representing cell shapes and tissue layers within the epithelium, constrain the model with state-of-the-art experimental cell biology and mechanobiology measurements, and then test quantitative model predictions for global tissue behavior. The work focuses on two objectives. In Objective 1 the team will use a first-of-its kind layered 3D vertex model to study the properties of the barrier/interface between the basal and suprabasal layer in both wildtype and knockout stratified epithelia, testing the hypothesis that heterotypic interactions between the two cell types and the basement membrane generate an effective mechanical barrier, and isolating how specific proteins contribute to that barrier. In Objective 2 the team will extend the 3D vertex model to study dynamic motion of cells across the barrier to understand how cell division, cell death, adhesion changes, and active cell migration drive delamination (i.e., allow cells from the basal layer to move to the suprabasal layer). The hypothesis that specific, cell-autonomous processes inside delaminating cells work together, possibly via mechanosensitive feedback loops, with tissue-scale mechanical processes (such as cell-division-driven unjamming) to precisely regulate cross-layer motion will be tested.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.

皮肤是由多种成分和细胞类型组成的生物组织，它们协同工作以执行关键功能，例如对外部环境形成灵活的屏障和愈合伤口。为了执行这些功能，皮肤有多个层-底层由可以分裂和转化为其他细胞类型的细胞组成，顶层的细胞很少分裂，具有特定的形状和特定的任务。最近的研究表明，这些细胞类型之间的机械相互作用有助于保持细胞层分离并调节细胞分裂，但很少有定量模型来仔细验证这一假设。该项目将为皮肤层开发一种新的生物物理计算模型，该模型考虑了细胞之间的机械相互作用。与细胞生物学实验合作，这项研究将把模型参数与特定生物分子的表达联系起来，如粘附分子或细胞骨架的成分。然后，它将预测细胞和组织的形状，以及细胞随着时间的推移离开底层更新组织的速率。这些预测将在实验中得到验证。最后，它将测试细胞感知通过组织传输的机械信号并因此改变粘附和细胞骨架分子的产生的假设，从而产生有助于正确调节组织生长和预防疾病的机械反馈回路。研究人员将提供一个公开可用的3D上皮组织模拟代码，让STEM领域的学生参与研究和专业发展经验，并传播关于建模细胞力学的讲座和计算练习。该项目的目标是使用哺乳动物皮肤作为模型系统，对自我更新的分层上皮细胞的机械响应进行定量预测和测试。该项目将开发一种新型的3D计算模型，代表上皮内的细胞形状和组织层，用最先进的实验细胞生物学和机械生物学测量来约束模型，然后测试定量模型对全球组织行为的预测。这项工作侧重于两个目标。在目标1中，该团队将使用第一种分层3D顶点模型来研究野生型和敲除分层上皮细胞中基底层和基底上层之间的屏障/界面的特性，测试两种细胞类型和基底膜之间的异型相互作用产生有效机械屏障的假设，并分离特定蛋白质如何有助于该屏障。在目标2中，该团队将扩展3D顶点模型以研究细胞跨越屏障的动态运动，以了解细胞分裂、细胞死亡、粘附变化和主动细胞迁移如何驱动分层（即，允许细胞从基底层移动到基底上层）。脱层细胞内部特定的细胞自主过程可能通过机械敏感反馈回路与组织尺度的机械过程（如细胞分裂驱动的解干扰）一起工作，以精确调节跨层运动的假设将被测试。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。