Analyzing and engineering dynamic control of population size during T cell expansion

项目摘要/摘要 当T细胞感觉到感染时，它会经历爆炸性的增殖。然而，这种扩散是暂时的。 并且不会过度延续成为癌症。这种对细胞分裂的精细控制是怎么可能的？ 尽管我们熟悉参与这一过程的基因，但我们对 这些基因是如何结合成电路的，从而实现精确的时间控制。 这个群体大小控制的问题对于改进收养细胞转移也具有实际意义 癌症的免疫疗法，一种日益成功的技术，通过这种技术，个人的T细胞 针对癌症进行了重新设计。现有的工程化T细胞不能为临床医生提供仔细 控制它们的数量--类似于一种无法控制剂量的药物。因此，副作用 与不充分或过度扩散相关的疾病都可能发生。 为了加深我们对T细胞种群扩大的了解，我建议在 哪些新的遗传电路将在T细胞中人工构建，从而控制种群数量 人工的和动态的。促进细胞分裂或死亡的蛋白质将由细胞在 对化学刺激的反应，这些生长和死亡成分将以不同的方式结合在一起 在细胞群体中创建不同的用户可调行为。使用这些系统，我计划确定 遗传电路设计与由此产生的种群扩张和动力的关系 收缩。 拟议的研究将提供对以下监管要素类型的概括性描述 会产生不同的种群规模动态。其中一些合成电路本身可能会被证明是有用的 为癌症开发新型工程化T细胞疗法的工具。此外，这些关系 此处的发现可能有助于阐明管理本地增殖控制连接的设计原则 系统。

Project Summary/Abstract When a T cell senses an infection, it undergoes explosive proliferation. However, this proliferation is transient and does not continue excessively to become cancer. How is such exquisite control of cell division possible? Although we are familiar with the genes that are involved in this process, we are still relatively uninformed as to how these genes are combined into circuits that enable precise temporal control. This question of population size control also has practical relevance for improving adoptive cell transfer immunotherapy for cancer, an increasingly successful technique whereby an individual's T cells are reengineered to target cancer. Existing engineered T cells do not furnish clinicians with the ability to carefully regulate their numbers—similar to a drug without the ability to control dosage. Consequently, side effects associated with either insufficient or over-proliferation can occur. To enhance our understanding of T cell population expansion, I propose to take an engineering approach in which new genetic circuits will be synthetically constructed in T cells that allow population size to be controlled artificially and dynamically. Proteins that promote either cell division or death will synthesized by the cells in response to chemical stimuli, and these growth and death components will be combined in different ways to create different user-adjustable behaviors in cell populations. Using these systems, I plan to determine the relationship between genetic circuit design and the resulting dynamics of population expansion and contraction. The proposed research will provide a generalizable characterization of the types of regulatory elements that can produce different population size dynamics. Some of these synthetic circuits themselves may prove useful tools in the development of new engineered T cell therapies for cancer. Furthermore, the relationships uncovered here may shed light on the design principles governing the wiring of native proliferative control systems.