EFRI:MIKS: NOTCH Signaling in Colon Cancer Stem Cells

由研究和创新新兴前沿办公室颁发的NSF奖项支持了解单个细胞中的动态信号传导和细胞命运决定电路如何引起多细胞系统水平的行为，如发育模式形成，以及这些电路的扰动如何导致不良后果，如癌症。这些问题将使用三种综合方法来解决：（a）在生理相关环境中跟踪干细胞行为的物理设备;（B）细胞命运决定电路的数学建模;（c）能够阐明基本设计原则的合成遗传电路工程。在目标1中，将开发包括体外微尺度装置和体内小鼠归巢模型的集成平台，以在生理现实环境中跟踪信号动力学和细胞命运决定。在目标2中，将表征信号动力学以开发结肠隐窝中模式形成的数学模型。这些模型将有助于解释实验数据和预测扰动结果。 在目标3中，基于Notch信号传导和细菌群体感应组件的合成电路将在结肠癌干细胞中实施，以形成从头模式，这将使用目标1的集成平台进行测试。（a）促进生物医学应用，（B）产生用于探索多细胞图案化系统的广泛有用的工具，以及（c）通过主要研究者和其他团队成员的具体活动对科学教育产生直接影响。促进治疗学的发展。模型系统，结肠癌干细胞，对常规化疗有抵抗力。开发有效的治疗方法，专门针对癌症干细胞，而不损害正常干细胞将需要更深入地了解控制自我更新，分化和稳态在正常和癌症干细胞的基础电路。 这里开发的物理设备可以进一步开发成高通量药物筛选平台;合成构建体可以用于研究不同细胞类型中的信号传导机制;小鼠归巢模型可以进行人体结肠干细胞和CRC肿瘤发生的体内研究。使用拟议研究中的材料，PI将共同教授系统和合成生物学课程中的哺乳动物系统的合成生物学和数学建模。这些材料还将被纳入正在开发的合成生物学教科书中。拟议的项目将被用作K-12外联讲座的一个例子。最后，该项目的物理设备和数学模型的简化版本将被用作CURIE学院的教学工具，该学院是一个为期一周的夏季住宿计划，重点是创造一个互动的氛围，让女高中生参与工程。

This NSF award by the Office of Emerging Frontiers in Research and Innovation supports work to understand how dynamic signaling and cell fate decision circuits in individual cells give rise to multicellular system-level behaviors such as developmental pattern formation and how perturbations to these circuits lead to undesirable consequences such as cancer. These questions will be addressed using three integrated methods: (a) Physical devices for tracking stem cell behaviors in a physiologically relevant environment; (b) Mathematical modeling of cell fate decision circuits; and (c) Engineering of synthetic genetic circuits capable of elucidating fundamental design principles.Intellectual meritThe team will study the role of intercellular Notch signaling in intestinal colon crypt formation and colorectal tumorigenesis. In Goal 1, an integrated platform including in vitro microscale devices and in vivo mouse homing models will be developed to track signaling dynamics and cell fate decisions in a physiologically realistic environment. In Goal 2, signaling dynamics will be characterized to develop mathematical models of pattern formations in colon crypts. These models will help interpret experimental data and predict perturbation results. In Goal 3, synthetic circuits based on Notch signaling and bacterial quorum sensing components will be implemented in colon cancer stem cells to form de novo patterns, which will be tested using the integrated platform from Goal 1.Broader impactThis work will have three main broader impacts: (a) facilitating biomedical applications, (b) generating broadly useful tools for the exploration of multicellular patterning systems, and (c) direct impacts on science education through specific activities of the principal investigators and other team members.Facilitating development of therapeutics. The model system, colon cancer stem cells, is resistant to conventional chemotherapies. Developing effective therapeutics that specifically target cancer stem cells without damaging normal stem cells will require a deeper understanding of the underlying circuits that control self-renewal, differentiation and homeostasis in normal and cancer stem cells.Tools for understanding differentiation and patterning. The physical devices developed here can be further developed into high throughput drug screening platforms; the synthetic constructs can be used to study signaling mechanisms in diverse cell types; and the mouse homing models enable in vivo studies of human colon stem cells and CRC tumorigenesis.Educational activity. Using materials from the proposed study, the PIs will work together to teach synthetic biology and mathematical modeling for mammalian systems in systems and synthetic biology courses. The materials will also be included in a synthetic biology textbook in development. The proposed project will be used as an example for K-12 outreach lectures. Finally, simplified versions of the physical devices and the mathematical model from this project will be used as teaching tools for the CURIE Academy, which is a one-week summer residential program focused on creating an interactive atmosphere to engage female high school students in engineering.