Designing complex living systems for monitoring and responding to disease progression

项目摘要 基于细胞的疗法在癌症治疗方面显示出巨大的潜力，但在电路设计方面存在局限性 已经阻止了它们对各种疾病的适用性。目前的治疗细胞只以二元方式对 相对较高水平的瞬时信号；此外，基因疗法只向细胞传递一种遗传元素，即 限制了他们执行复杂功能的能力，从而限制了他们的适用性。开发新型细胞系统 能够响应不同的生物标志物并制定多种独立调节的电路元件是至关重要的 扩大了细胞疗法的范围。 这项工作旨在设计新的传感器、绝缘体元件和计算模型 创建系统来调节炎症的背景，主要是因为慢性炎症具有 在多种疾病的进展中起着突出的作用。调查的一个方面将探索如何 细胞可以在延长的时间段内整合炎症信号，以及细胞如何基于 在所经历的总信号上。由此产生的工程化细胞传感器可以作为开发 使用依赖时间的生物标志物治疗慢性炎症和其他疾病。的另一个方面 调查将探索将遗传绝缘体和反沉默方法结合到 合成电路。将多个差异调控的遗传元件整合到单个电路中是 具有挑战性，因为真核转录因子可以远距离发挥作用。确定一组绝缘子 不会与其他人发生交叉反应，将有助于创建在综合体中使用绝缘子的通用框架 基因回路，并有助于创造更复杂的遗传回路。此外，由于表观遗传学 随着时间的推移，沉默会降低基因治疗的活性和有效性，研究如何减少 沉默--通过绝缘体和其他基因修饰--将有助于创造出延长寿命的方法 细胞和基因疗法。调查还将使用计算模型来探索相互作用 反应灵敏的合成细胞和药代动力学之间的关系。该模型将包含炎性细胞信号， 合成抗体的生产和系统水平的分布，以指导治疗细胞的设计 调节炎症。综上所述，拟议的工作将有助于阐明细胞传感和 基因调控，这是开发新的基于细胞的疗法的关键步骤。

Project Summary Cell-based therapies have shown great potential for cancer treatment, but limitations in circuit design have prevented their applicability to diverse diseases. Current therapeutic cells only respond in a binary way to relatively high levels of a transient signal; further, gene therapies deliver only one genetic element to cells, which limits their abilities to perform complex functions and thus their applicability. Developing new types of cell systems that can respond to diverse biomarkers and enact multiple, independently regulated circuit elements is critical for expanding the scope of cell therapies. The work proposed here aims to design novel sensors, insulator elements, and computational models in the context of creating systems to modulate inflammation, primarily because chronic inflammation has a prominent role in the progression of multiple diseases. One aspect of the investigation will explore ways that cells can integrate inflammatory signals over extended time periods and how cells differentially respond based on the total signal experienced. The resulting engineered cell sensors could serve as a basis for developing therapies for chronic inflammation and other diseases with time-dependent biomarkers. Another aspect of the investigation will explore ways that genetic insulators and anti-silencing methods can be incorporated into synthetic circuits. Incorporating multiple, differentially-regulated genetic elements onto single circuits is challenging, as eukaryotic transcription factors can act across long distances. Determining a set of insulators that do not cross-react with others will help to create a generalizable framework for using insulators in complex genetic circuits, and help to enable the creation of more complex genetic circuits. Further, since epigenetic silencing decreases the activity and effectiveness of gene therapies over time, investigating ways to reduce silencing—through insulators and other genetic modifications—will help to create ways to improve the longevity of cell and gene therapies. The investigation will also use computational modeling to explore the interplay between responsive synthetic cells and pharmacokinetics. The model will incorporate inflammatory cell signaling, synthetic antibody production, and systems-level distribution to guide the design of therapeutic cells that modulate inflammation. Taken together, the proposed work will help to elucidate methods of cell sensing and gene regulation, which are critical steps for developing new classes of cell-based therapies.