CAREER: History-Dependent Cell Motility in Heterogeneous Microenvironments

这个NSF教师早期职业发展（CAREER）计划奖的研究目标是了解细胞如何在不同硬度的组织中移动，以到达体内的遥远位置。细胞在活组织中单独和一起移动的能力从根本上控制着我们的身体在健康和疾病中的功能，包括发育，衰老和癌症等疾病。 在整个生命周期中，细胞根据复杂的程序在时间和空间中移动。虽然已经单独研究了该过程的各个步骤，但尚不清楚细胞迁移过程的多个步骤是否相互依赖。这项研究将通过一种创新的多学科方法来解决这些悬而未决的问题，该方法结合了微制造，生物材料，细胞生物学和计算机模拟。这些研究将揭示组织的机械特性如何调节细胞作为个体和群体的运动方式，这反过来将有助于创建工程细胞运动的新策略。这些研究工作将与教育和推广计划相结合，以制定一个框架，用于在工程和生物学的界面上培训和教育研究生，本科生和K-12学生。关于异质环境中细胞表型变化的时间和长度尺度的知识可能有助于更好地预测细胞如何侵入复杂组织。为了实现这一研究目标，该项目将采用基于工程的方法，允许系统的“时间和空间”解构细胞内和细胞外参数。这些研究将包括制造可调机械性能的组织模拟细胞培养平台，研究不同性质基质中的细胞运动性，以及构建模拟不同环境中单个和集体细胞迁移的计算模型。附带的教育计划强调了基于工程的方法通常是如何独特地适合于研究复杂的生物过程。教育活动将通过一个综合社区外展计划培训学生细胞机械生物学，该计划包括一个机器人细胞爬行展览和相应的高中生教学模块。研究工作中的计算机模拟和细胞运动视频将被纳入教学模块，并提供给合作高中的科学教师。教育计划还包括关于“细胞运动力学”的本科生和研究生课程开发，以及为一年级学生提供本科生研究实习机会，以鼓励在早期阶段进行多学科学习。

The research objective of this NSF Faculty Early Career Development (CAREER) Program award is to understand how cells move across tissue of varying stiffness to reach distant locations within the body. The ability of cells to move, both singly and together, through living tissue fundamentally controls how our bodies function in health and disease, including development, aging, and disorders such as cancer. Throughout their life cycle, cells move in time and space according to a complex program. While various steps of this process have been studied separately, it is not well understood if multiple steps of the cell migration process are interdependent. This research will tackle these unanswered questions through an innovative multi-disciplinary approach that combines micro-fabrication, biomaterials, cell biology, and computer simulation. These studies will reveal how mechanical properties of the tissue regulate how cells move, both as individuals and groups, which in turn will help create new strategies to engineer cell motion. These research efforts will be combined with an education and outreach plan to develop a framework for training and educating graduate, undergraduate, and K-12 students at the interface of engineering and biology. The knowledge about time and length scales of changes in cellular phenotypes across heterogeneous environments might enable better predictions of how cells invade complex tissue. Towards this research goal, the project will employ engineering-based approaches that allow systematic "time and space" deconstruction of intra- and extra-cellular parameters. These studies will include fabrication of tissue-mimetic cell culture platforms of tunable mechanical properties, study of cell motility across matrices of varying properties, and construction of computational models simulating single and collective cell migration in diverse environments. The accompanied education plan highlights how engineering-based approaches are often uniquely suited to study complex biological processes. The education activities will train students in cellular mechanobiology through an integrated community outreach program consisting of a robotic cell-crawling exhibit and corresponding teaching modules for high-school students. The computer simulations and cell motility videos from research efforts will be included in the teaching modules and made available to science teachers from partner high schools. The education plan also includes undergraduate and graduate course development on "mechanics of cell motility" and undergraduate research internships for first year students to encourage multidisciplinary learning at an early stage.