Epithelial Cell Mechanobiology in Mechanically Heterogeneous Microenvironments

机械异质微环境中的上皮细胞力学生物学

• 批准号: 10226378
• 负责人: Amit Pathak
• 金额: $ 39.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226378
• 关键词: 3-Dimensional; Basement membrane; Cells; Collection; Computer Models; Cytoskeletal Modeling; Defect; Development; Disease; Distant; Environment; Epithelial; Epithelial Cells; Evolution; Extracellular Matrix; Fibrosis; Heterogeneity; Malignant Neoplasms; Measures; Mechanics; Mesenchymal; Morphogenesis; Nuclear; Outcome; Pharmacology; Process; Property; Research; Shapes; Tissues; Tumor Cell Invasion; Work; base; cell behavior; experimental study; migration; novel; novel therapeutic intervention; response; simulation

PROJECT SUMMARY During development and disease, epithelial cells can migrate collectively, with or without undergoing epithelial- mesenchymal transition (EMT), through heterogeneous matrices, enabling fundamental processes such as branching morphogenesis, fibrosis, and tumor invasion. We have shown that extracellular matrix (ECM) properties beyond the current ECM stiffness, such as confinement and past ECM stiffness, can fundamentally alter epithelial responses. Through a collection of projects, combining experiments and simulations, this proposal will reveal new modes collective cell behaviors in matrices of heterogeneous stiffness and topography. We will measure EMT and migration of epithelial cells around defects in a basement membrane (BM)-like matrix, determine 3D invasion due to defect-induced EMT, build a computational model to understand rate-dependent EMT evolution, and pharmacologically disrupt BM degradation. We will also assess whether the epithelial cells can sense deeply into their matrix and alter responses based on distant stiffening of the matrix. In another project, we will investigate how cell sheets migrate in 3D-like confined environments of tunable stiffness and topography. We will connect nuclear shape with cytoskeletal reorganization to understand how cells adapt to distinct stiffnesses of past and present matrices. Outcomes of these projects will enable new fundamental understanding of epithelial cell responses to matrix heterogeneities that have remained unexplored and could reveal novel targets for diseases such as fibrosis and cancer.

项目概要 在发育和疾病过程中，上皮细胞可以集体迁移，无论是否经历上皮- 间充质转化 (EMT)，通过异质基质，实现以下基本过程： 分支形态发生、纤维化和肿瘤侵袭。我们已经证明细胞外基质（ECM） 超出当前 ECM 刚度的特性，例如约束和过去的 ECM 刚度，可以从根本上 改变上皮反应。通过一系列项目，结合实验和模拟，这 该提案将揭示异质刚度矩阵中集体细胞行为的新模式 地形。我们将测量基底膜缺陷周围上皮细胞的 EMT 和迁移 (BM) 类矩阵，确定由于缺陷引起的 EMT 导致的 3D 侵入，建立计算模型 了解速率依赖性 EMT 进化，并通过药理学破坏 BM 降解。我们还将评估 上皮细胞是否可以深入感知其基质并根据远处的硬化改变反应 矩阵。在另一个项目中，我们将研究细胞片如何在类似 3D 的受限环境中迁移 可调刚度和形貌。我们将把核形状与细胞骨架重组联系起来来理解 细胞如何适应过去和现在基质的不同硬度。这些项目的成果将使新的 对上皮细胞对基质异质性反应的基本理解仍然存在 未经探索，可能揭示纤维化和癌症等疾病的新靶点。