CAREER: Directing Epithelial-Mesenchymal Tissue Self-Structuring and Remodeling With Multi-scale Mechanical Interactions and Principles of Mechanobiology

NSF学院早期职业发展(Career)计划赠款的目标是建立一个综合的研究和教育计划，以了解物理力量如何对上皮-间充质结构(EMS)的初始形成和后来的变化做出贡献，例如皮肤的双层表皮和真皮结构。这些结构存在于大多数身体组织中，它们对组织健康至关重要。在组织形成的过程中，细胞与细胞和细胞与细胞外基质的相互作用结合在一起，形成了具有EMS的有组织、有功能的组织。然而，在生命的后期，这些组织对损伤、疾病或衰老的反应能力有限。为医学目的指导组织自组织和重塑的努力正在取得进展，但由于不知道细胞和基质之间的相互作用如何在生化和机械上协调以产生健康的组织，这些努力仍然受到阻碍。这些交互是复杂的，并产生使用简单方法不容易理解的行为。这项研究将提供一个基本的计算机模型，它可以将来自不同实验的数据和观察结果整合到一张统一的图片中，以便理解和使用机械生物学的基本原理来帮助控制组织的形成和重塑。该项目有望在皮肤上皮-间充质相互作用中物理力的作用方面产生新的发现和见解。所获得的知识和开发的工具也可能广泛适用于发生EMS的身体其他部位，如血管、肺、肠和肾脏。该项目更广泛的目标包括使公众更多地了解、理解和兴奋如何使用数学、工程和计算机建模来简化复杂的生物过程，特别是那些涉及机械力的过程。该项目的研究成果将与爱荷华大学的推广项目合作，放入K-12年级的年轻学生可以使用的学习模块中。研究还将投入本科生和研究生的生物医学工程课程，以及公众可访问和免费下载的带有实时细胞成像和计算机模拟的多媒体电子书。体外角质形成细胞和成纤维细胞的延时成像实验将用于开发和调整多尺度计算模型，以了解和预测物理力量如何驱动EMS在皮肤中的自我结构和重塑。这将通过：(1)量化基质硬度、成分和负载环境对角质形成细胞机械传感和自组装过程的影响；(2)开发基于机械网络的角质形成细胞机械传感模型，该模型与现有的多尺度模型接口；(3)检验假设，即角质形成细胞和真皮成纤维细胞之间的机械串扰影响工程皮肤系统中的自结构和EMS的形成；以及(4)扩展细胞模型以包括3D成纤维细胞驱动的重建。

The goal of this NSF Faculty Early Career Development (CAREER) Program grant is to establish an integrated research and education program centered on understanding how physical forces contribute to the initial formation and later changes in epithelial-mesenchymal structures (EMS), such the bi-layered epidermal and dermal structure of skin. These structures are present in most body tissues and they are critical to tissue health. During the process of tissue formation, cell-to-cell and cell-to-extracellular matrix interactions combine to produce organized, functional tissues with EMS. Later in life, however, these tissues have limited capacity to regenerate themselves in response to injury, disease, or aging. Efforts to direct tissue self-structuring and remodeling for medical purposes are progressing, but they are still hampered by not knowing how the interactions between cells and matrix are coordinated biochemically and mechanically to produce a healthy tissue. These interactions are complex and produce behaviors that cannot be easily understood using a simple approach. This research will provide an essential computer model that can incorporate data and observations from different experiments into a unified picture so that basic principles of mechanobiology can be understood and used to help control tissue formation and remodeling. The project is expected to produce new discoveries and insights on the role of physical forces in epithelial-mesenchymal interactions in skin. The knowledge gained and tools developed may also be broadly applicable and useful to other parts of the body where EMS occur, such as blood vessels, lungs, intestines, and kidneys. Broader goals of the project include generating more public awareness, understanding, and excitement for how mathematics, engineering, and computer modeling can be used to simplify complex biological processes, particularly those that involve mechanical forces. Research findings from this project will be put into learning modules accessible for young students from K-12 in collaboration with the University of Iowa outreach programs. Research will also be put into undergraduate and graduate biomedical engineering courses, and into a publically accessible and freely downloadable multimedia iBook with live cell imaging and computer simulations.In vitro time-lapse imaging experiments on keratinocytes and fibroblasts will be used to develop and tune a multi-scale computational model for understanding and predicting how physical forces drive self-structuring and remodeling of EMS in skin. This will be accomplished by: (1) quantifying the effect of substrate stiffness, composition, & loading environment on mechanosensing and the self-assembly process of keratinocytes; (2) developing a mechanistic network-based model of mechanosensing keratinocytes that interfaces with an existent multi-scale model; (3) testing the hypothesis that mechanical crosstalk between keratinocytes and dermal fibroblasts influences self-structuring and EMS formation in an engineered skin system; and (4) extending the cell model to include 3D fibroblast-driven remodeling.