Design-driven engineering of robust mammalian sense-and-respond functions

项目摘要 该项目的最终目标是使工程细胞疗法的使用能够安全和 有效治疗从癌症到自身免疫性疾病，再到那些需要再生的疾病 医药。工程细胞疗法代表了医学的一个令人兴奋的前沿，也是该领域的早期成功。 已经证明了这种方法的变革潜力，使治疗癌症成为可能 没有现有治疗方法有效的患者。然而，充分实现工程细胞的前景 治疗将需要技术和工具，使生物工程师能够有效地设计、建造和评估 满足特定临床需求的定制细胞功能。而哺乳动物合成生物学领域 已经朝着这个目标迈出了令人印象深刻的一步，将基础科学转化为临床强加了一套新的 设计和工程挑战。特别是，新的实验技术和计算工具 需要以一种能够带来强劲表现的方式设计细胞疗法-成功地执行 治疗计划，尽管不可避免的生物变异。 为了满足这一需求，该团队将开发一套完整的新实验试剂，新的 计算工具和新的概念理解，以加速实施设计驱动 通过使生物工程师能够对细胞进行编程，以感知、评估和响应环境，从而实现医学 新颖、实用、可靠的方式。该团队最近开发了一种名为Mesa的合成生物学技术 受体蛋白，使人能够“重新连接”细胞感知宿主生理特征的方式。这个项目 包括一个重要的桥梁，从一个有前途的战略的早期演示到真正的 生物工程界可以很容易地应用于设计和建造的技术平台 新的细胞疗法。这个项目的目标是由团队在工程设计方面的丰富经验所决定的 受体技术，该项目解决了哺乳动物合成生物学中的一般挑战。第一 目标是开发设计细胞感知功能的策略，使其在不可避免的情况下稳健运行 生物变异。这一目标包括计算模型指导的蛋白质和基因设计 组件，使细胞传感功能对生物工程更有用。这项工作将包括 MESA与其他工程传感平台的比较。第二个目标是建立一个小说图书馆 对生理相关提示做出反应的台面生物传感器。这一目标的结果将包括更好的 了解如何构建生物传感器，以及使生物工程师能够 立即将这项技术用于治疗应用。第三个目标是评估和发展 在多种细胞类型中实现工程化生物传感功能的策略，包括稳定的 细胞系和原代细胞，通过翻译相关的基因传递平台进行比较。

Project Summary The ultimate goal of this project is to enable the use of engineered cell therapies to safely and effectively treat conditions ranging from cancer, to autoimmune disease, to those requiring regenerative medicine. Engineered cell therapies represent an exciting frontier in medicine, and early successes in the field of cancer treatment have demonstrated the transformative potential of this approach, enabling the treatment of patients for whom no existing therapy was effective. However, fully realizing the promise of engineered cell therapies will require technologies and tools that enable bioengineers to efficiently design, build, and evaluate customized cellular functions that meet specific clinical needs. While the field of mammalian synthetic biology has made impressive strides toward this goal, translating basic science to the clinic imposes a new set of design and engineering challenges. In particular, new experimental technologies and computational tools are needed to design cell therapies in a way that leads to robust performance—the successful execution of a therapeutic program despite inevitable biological variability. To meet this need, this team will develop an integrated suite of new experimental reagents, new computational tools, and new conceptual understanding to accelerate the implementation of design-driven medicine by enabling bioengineers to program cells to sense, evaluate, and respond to their environment in novel, useful, and reliable ways. The team recently developed a synthetic biology technology called MESA receptor proteins, which enable one to “rewire” how a cell senses features of host physiology. This project comprises a crucial bridge from an early demonstration of a promising strategy to the development of a true technology platform that may be readily applied by the bioengineering community to design and construct novel cell therapies. The goals of this project are informed by the team's substantial experience in engineered receptor technologies, and this project addresses general challenges in mammalian synthetic biology. The first Aim is to develop strategies for engineering cellular sensing functions that perform robustly across inevitable biological variation. This aim comprises computational model-guided design of proteins and genetic components to make cellular sensing functions more useful for bioengineering. This work will include a comparison of MESA with other engineered sensing platforms. The second Aim is to develop a library of novel MESA biosensors that respond to physiologically relevant cues. Outcomes of this aim will include a better understanding of how to build biosensors, as well as a panel of reagents that enable bioengineers to immediately employ this technology for therapeutic applications. The third Aim is to evaluate and develop strategies for implementing engineered biosensing functions in a wide range of cell types, including both stable cell lines and primary cells, with comparisons across translationally-relevant gene delivery platforms.