Design-driven engineering of robust mammalian sense-and-respond functions: from parts to programs

强大的哺乳动物感知和响应功能的设计驱动工程：从零件到程序

• 批准号: 10682086
• 负责人: Neda Bagheri
• 金额: $ 61.54万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682086
• 关键词: Achievement; Address; Area; Autoimmune Diseases; Award; Behavior; Biological; Biomedical Engineering; Biosensing Techniques; Cell Line; Cell Therapy; Cell physiology; Cells; Chromatin; Clinical; Communities; Complex; Computer Assisted; Computer-Aided Design; Cues; Data; Development; Engineering; Environment; Epigenetic Process; Evaluation; Exhibits; Genetic; Genetic Transcription; Genome; Goals; Human; Imagination; Knowledge; Libraries; Malignant Neoplasms; Mammalian Genetics; Maps; Medicine; Memory; Methods; Modeling; Natural Killer Cells; Population; Positioning Attribute; Process; Progress Reports; Protein Engineering; Proteins; Regenerative Medicine; Reporting; Research; Research Personnel; Resources; Safety; Site; Software Framework; System; Technology; Therapeutic; Time; Tumor Markers; Work; cancer immunotherapy; cancer therapy; cellular engineering; computer framework; computerized tools; design; effective therapy; engineered T cells; engineering design; frontier; functional outcomes; genetic architecture; graphical user interface; improved; insight; multi-scale modeling; novel; novel therapeutics; programs; receptor; sensor; success; synthetic biology; technology development; tool; transcription factor

Project Summary The overarching goal of this project is to enable the use of engineered cell therapies to safely and effectively treat conditions ranging across cancer, autoimmune disease, and regenerative medicine. Engineered cell therapies are an exciting frontier, with early successes in cancer treatment demonstrating the transformative potential of this approach. Customized cell therapies could yield safe and effective treatments for many applications beyond cancer, but realizing this potential is limited by the fact that evaluating a potential therapeutic strategy requires extensive time and resources to implement it. The goal of this project is to flip this paradigm— to enable spending less time building and thus focus on evaluating potentially useful strategies. This project will develop state-of-the-art technologies for cell engineering and enable their application to solve three open, complementary, clinically motivated challenges. The first aim is to develop the technology, understanding, and computational tools required to build genetic programs that employ natural mechanisms for implementing long-lived memory. Natural systems employ genetic memory to drive processes such as differentiation and development by adding and removing stable marks to the genome. Although research has yielded insights into how to drive such changes, bioengineers do not yet have the ability to leverage those insights to build programs that implement these effects for useful purposes. This project will address this need by developing genetic programs that exhibit stable behaviors including inducible and autonomous state switching. The second aim will generate novel candidate cell therapies for treating cancer that leverage foundational advances for engineering cells to evaluate and respond to external cues (e.g., unique markers of the tumor site) to induce desired therapeutic behaviors. This work will develop programs hypothesized to improve both safety and efficacy of these approaches. A key aspect of this work is employing model-guided design to evaluate and refine genetic programs to confer desired behaviors. The third aim will develop a computational framework enabling computer-assisted design of genetic programs. Current design is limited by the imagination of the designer—a human must propose a design which is subsequently evaluated. This aim will make the transformative leap to semi-automated design, establishing workflows and tools that are freely accessible to researchers in a graphics-enabled open software framework.

项目摘要 该项目的总体目标是使工程细胞疗法的使用能够安全有效地 治疗癌症、自身免疫性疾病和再生医学等疾病。工程化细胞 癌症治疗是一个令人兴奋的前沿领域，癌症治疗的早期成功证明了 这种方法的潜力。定制的细胞疗法可以为许多人提供安全有效的治疗 癌症以外的应用，但实现这一潜力是有限的事实，评估一个潜在的治疗， 战略需要大量的时间和资源来实施。本项目的目标是扭转这种模式- 以使得能够花费更少的时间来构建，从而专注于评估潜在有用的策略。 该项目将开发最先进的细胞工程技术，并使其应用能够解决 三个开放互补的临床挑战第一个目标是发展技术， 理解和计算工具，需要建立遗传程序，采用自然机制， 实现长寿命记忆。自然系统利用遗传记忆来驱动诸如 通过在基因组中添加和去除稳定的标记来分化和发育。虽然研究表明， 虽然生物工程师们对如何推动这些变化有了深入的了解，但他们还没有能力利用这些变化， 洞察力，以建立程序，实现这些效果的有用的目的。本项目将满足这一需求 通过开发表现出稳定行为的遗传程序，包括诱导和自主状态， 切换第二个目标将产生用于治疗癌症的新型候选细胞疗法， 工程细胞评估和响应外部线索的基础进展（例如，独特的标志物 肿瘤部位）以诱导期望的治疗行为。这项工作将开发假设的程序，以改善 安全性和有效性。这项工作的一个关键方面是采用模型引导设计， 评估和改进遗传程序，以赋予所需的行为。第三个目标是开发一个计算 框架，使计算机辅助设计的遗传程序。目前的设计受到想象力的限制 设计师的一个人必须提出一个设计，随后进行评估。这一目标将使 向半自动化设计的变革性飞跃，建立可免费访问的工作流程和工具， 研究人员在一个图形支持的开放软件框架。

项目成果

The evolution of synthetic receptor systems.

• DOI: 10.1038/s41589-021-00926-z
• 发表时间: 2022-03
• 期刊: NATURE CHEMICAL BIOLOGY
• 影响因子: 14.8
• 作者: Manhas, Janvie;Edelstein, Hailey, I;Leonard, Joshua N.;Morsut, Leonardo
• 通讯作者: Morsut, Leonardo

Control of mammalian cell-based devices with genetic programming.

通过基因编程控制基于哺乳动物细胞的设备。

• DOI: 10.1016/j.coisb.2021.100372
• 发表时间: 2021
• 期刊: Current opinion in systems biology
• 影响因子: 3.7
• 作者: Dray,KateE;Edelstein,HaileyI;Dreyer,KathleenS;Leonard,JoshuaN
• 通讯作者: Leonard,JoshuaN

GAMES: A Dynamic Model Development Workflow for Rigorous Characterization of Synthetic Genetic Systems.

• DOI: 10.1021/acssynbio.1c00528
• 发表时间: 2022-02-18
• 期刊: ACS SYNTHETIC BIOLOGY
• 影响因子: 4.7
• 作者: Dray, Kate E.;Muldoon, Joseph J.;Mangan, Niall M.;Bagheri, Neda;Leonard, Joshua N.
• 通讯作者: Leonard, Joshua N.

Teaching systematic, reproducible model development using synthetic biology.

教授使用合成生物学进行系统的、可重复的模型开发。

• DOI: 10.18260/2-1-370.660-132665
• 发表时间: 2023
• 期刊: Chemical engineering education
• 作者: Dray,KateE;Dreyer,KathleenS;Lucks,JuliusB;Leonard,JoshuaN
• 通讯作者: Leonard,JoshuaN