Sentinels: A plug-and-play RNA sensing technology platform for surveillance and response to emerging viral diseases

细胞可以被编程为感知感染因子，并作为响应，启动生物分子程序以警告、保护宿主或破坏致病目标。以这种方式改造细胞将提供一种变革性的方法来解决新出现的病毒性疾病的威胁。该项目的目标是开发一种新的病原体检测平台，可以很容易地重新编程，以感知新的威胁，并作为回应，产生任何蛋白质输出。这项技术将提高我们设计用于各种诊断和治疗应用的哨兵细胞的能力。该项目还将提供教育和培训机会，旨在增加追求生物分子和细胞工程以及相关STEM领域职业的高中生和本科生的数量和多样性。作为该项目的一部分，将通过学生主导的倡议创建用于设计哨兵细胞的开源网络设计工具。基于RNA的传感器为编程细胞检测病原体提供了一个特别有吸引力的选择，因为它们依赖于可设计的RNA碱基配对相互作用，并能够检测RNA编码的基因组通过分析病原体和宿主的基因型（基因型）和mRNA（表型），可以潜在地更准确地读出感染状态。然而，目前缺乏可以将RNA输入与生物分子输出连接的遗传编码的RNA检测平台，从而排除了响应于特定RNA特征而执行哨兵程序的细胞装置的设计。为了解决这个问题，将探索生物分子和合成生物学策略，以创建即插即用的RNA传感和响应平台。将创建检测不同病毒相关RNA分子的设备，并作为响应，激活不同的生物分子程序来警告和摧毁病毒。这将直接应用于哨兵细胞设计，并可以很容易地用于基础科学，合成生物学和代谢工程的其他应用。该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

Cells can be programmed to sense infectious agents and, in response, actuate biomolecular programs to alert, protect the host, or destroy the pathogenic target. Engineering cells in this manner would provide a transformative approach to address the threat of emerging viral diseases. The goal of this project is to develop a novel pathogen detection platform that can be easily reprogrammed to sense new threats, and in response, produce any protein output. This technology will forward our ability to engineer sentinel cells for diverse diagnostics and therapeutic applications. This project will also provide educational and training opportunities aimed at increasing the number and diversity of high school students and undergraduates pursuing careers in biomolecular and cellular engineering, and related STEM fields. As part of this project open-source web-based design tools for designing sentinel cells will be created through a student-led initiative.RNA-based sensors present a particularly attractive option for programming cells to detect pathogens because they rely on designable RNA base pairing interactions and enable detection of RNA encoded genomes (genotypes) and mRNAs (phenotypes) of both the pathogen and host, allowing for potentially more accurate readouts of the infection status. However, there is currently a lack of genetically-encoded RNA detection platforms that can interface RNA inputs to biomolecular outputs, precluding the design of cellular devices that execute sentinel programs in response to specific RNA signatures. To address this, biomolecular and synthetic biology strategies to create plug-and-play RNA sense-and-respond platforms will be explored. Devices will be created that detect different virus associated RNA molecules, and, in response, activate diverse biomolecular programs to alert and destroy viruses. This will find direct applications for sentinel cell design and could be easily utilized for other applications in basic science, synthetic biology, and metabolic engineering.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.