CAREER: Learning and teaching how to program morphogenesis with synthetic genetic circuits, a case study for elongation of mammalian cell spheroids

在实验室里培育器官和多细胞机器是再生医学的前沿。然而，控制实验室生长材料的形状是难以捉摸的。创建一个计算框架，可以帮助设计控制网络，驱动细胞组自组装成细长的结构是这个项目的主要目标。支持课程和教师发展是另一个目标。在合成生物学方面举办讲习班和培训教师将有助于培养当地社区代表性不足的高中生对STEM领域的兴趣。主要目标是合理设计和自主制造轴向伸长的三维组织、器官和生物机器人。该研究的核心假设是，基于合成Notch （synNotch）接触依赖性细胞信号传导的人工遗传电路可以在硅上设计和优化，以控制体外生长的多细胞结构的轴向伸长，同时控制粘附和增殖。一个经过验证的基于增强细胞波茨模型的计算建模平台将用于开发遗传程序。这些程序将在成纤维细胞中实施。定量荧光成像将显示其维持伸长的能力。在该项目中开发的经过验证的预测计算平台将可用于更广泛的形状和结构。确定轴向伸长的遗传驱动因素将增加我们对正常发育过程的理解，并提供可能在某些出生缺陷的病理生理学中发挥作用的网络故障的见解，以及推进再生医学和软机器人技术中体外培养组织的控制。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Growing organs and multicellular machines in the lab is at the leading edge of regenerative medicine. However, controlling the shape of lab-grown materials is elusive. Creating a computational framework that can help design control networks to drive groups of cells to self-assemble into elongated structures is the primary objective of this project. Supporting curriculum and teacher development is another objective. Presenting workshops and training teachers in synthetic biology will help cultivate interest in STEM fields among under-represented high school students from local neighborhoods.The primary objective is to rationally design and autonomously manufacture axially elongated, three-dimensional tissues, organs and biobots. The central hypothesis is that artificial genetic circuits, based on synthetic Notch (synNotch) contact-dependent cell-cell signaling, could be designed and optimized in silico to control axial elongation of in vitro grown multicellular structures, when combined with control of adhesion and proliferation. A validated platform for computational modeling based on an augmented Cellular Potts model will be used to develop genetic programs. These programs will be implemented in fibroblasts. Quantitative fluorescent imaging will indicate their capacity to sustain elongation. The validated, predictive computational platform developed during this project will be available for use on a broader range of shapes and structures. Identification of genetic drivers of axial elongation will increase our understanding of normal developmental processes and provide insights into network malfunctions that may play a role in the pathophysiology of certain birth defects as well as advancing control of in vitro-grown tissues for applications in regenerative medicine and soft robotics.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.