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

T 细胞扩增过程中群体大小的分析和工程动态控制

• 批准号: 9192562
• 负责人: Nicholas Frankel
• 金额: $ 5.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9192562
• 关键词: Address; Adoptive Cell Transfers; Adverse effects; Antigens; Apoptosis; Behavior; Biological; Biological Models; Cause of Death; Cell Count; Cell Cycle; Cell Death; Cell division; Cells; Cessation of life; Chemicals; Clonal Expansion; Complex; Computer Simulation; Cyclin D1; Development; Drops; Engineering; Equilibrium; Excision; Future; Genes; Genetic; Goals; Growth; Heterogeneity; Homeostasis; Human; Immune; Immunology; Individual; Infection; Inflammation; Lead; Life; Light; Link; Malignant Neoplasms; Maps; Measurement; Measures; Modeling; Molecular; Obesity; Pharmaceutical Preparations; Physiologic pulse; Population; Population Control; Population Dynamics; Population Sizes; Process; Proteins; Regulatory Element; Research; Research Project Grants; Scanning; Signal Transduction; Stimulus; System; Systems Biology; T cell regulation; T cell therapy; T-Lymphocyte; Techniques; Therapeutic; Time; Up-Regulation; abstracting; behavioral response; cancer immunotherapy; cancer stem cell; cancer therapy; cell behavior; cellular engineering; cytokine; design; dosage; exhaust; fighting; genetic element; immunogenic; improved; insight; mathematical model; mathematical theory; non-Native; research study; response; synthetic biology; tool

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.

项目总结/摘要 当T细胞感觉到感染时，它会发生爆炸性增殖。然而，这种增殖是短暂的 并且不会继续过度发展成为癌症。如此精致的细胞分裂控制是如何实现的？ 虽然我们对参与这一过程的基因很熟悉，但我们仍然相对不了解， 这些基因是如何组合成电路来实现精确的时间控制的。 这个群体大小控制的问题对于改善过继细胞转移也具有实际意义 癌症免疫疗法是一种越来越成功的技术，通过这种技术， 针对癌症进行改造现有的工程化T细胞并不能为临床医生提供仔细检查 调节它们的数量--类似于没有控制剂量能力的药物。因此，副作用 可能发生与增殖不足或过度增殖相关的疾病。 为了加强我们对T细胞群体扩增的理解，我建议采取工程方法， 哪些新的遗传回路将在T细胞中合成构建，从而控制种群规模 人工地和动态地。促进细胞分裂或死亡的蛋白质将由细胞合成， 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起来， 在细胞群中创建不同的用户可调节行为。使用这些系统，我计划确定 基因电路设计和由此产生的种群扩张动态之间的关系， 收缩。 拟议的研究将提供一个可推广的表征类型的调节元件， 可以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 开发新的工程化T细胞治疗癌症的工具。此外，关系 这里揭示的可能揭示了控制天然增殖控制的设计原则， 系统.