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， 有效地治疗从癌症到自身免疫性疾病，再到需要再生的疾病 药工程细胞疗法代表了医学领域令人兴奋的前沿，以及该领域的早期成功 已经证明了这种方法的变革潜力，能够治疗 现有治疗无效的患者。然而，完全实现工程细胞的承诺， 治疗需要技术和工具，使生物工程师能够有效地设计，建造和评估 定制的细胞功能，以满足特定的临床需求。哺乳动物合成生物学领域 在实现这一目标方面取得了令人印象深刻的进展，将基础科学转化为临床， 设计和工程挑战。特别是，新的实验技术和计算工具， 需要设计细胞疗法的方式，导致强大的性能-成功执行一个 尽管不可避免的生物变异性。 为了满足这一需求，该团队将开发一套新的实验试剂， 计算工具和新的概念理解，以加速设计驱动的实施 通过使生物工程师能够编程细胞来感知，评估和响应它们的环境， 新颖、实用、可靠的方法。该团队最近开发了一种名为梅萨的合成生物学技术 受体蛋白质，使人们能够“重新连接”细胞如何感受宿主生理特征。这个项目 包括一个重要的桥梁，从早期展示一个有前途的战略， 技术平台，可以很容易地应用于生物工程界的设计和建设 新型细胞疗法该项目的目标是由团队的丰富经验，在工程 受体技术，该项目解决哺乳动物合成生物学的一般挑战。第一 目的是制定策略，工程细胞传感功能，执行稳健的跨越不可避免的 生物变异这一目标包括蛋白质和遗传学的计算模型指导设计 组件，使细胞传感功能更有用的生物工程。这项工作将包括 梅萨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 梅萨生物传感器对生理相关线索做出反应。这一目标的成果将包括一个更好的 了解如何构建生物传感器，以及一组试剂，使生物工程师能够 立即将该技术用于治疗应用。第三个目标是评价和发展 在广泛的细胞类型中实施工程生物传感功能的策略，包括稳定的 细胞系和原代细胞，并在免疫相关的基因递送平台上进行比较。

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.