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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要当 T 细胞感知到感染时，它会发生爆炸性增殖，但这种增殖是短暂的。并且不会继续过度发展成为癌症，这种对细胞分裂的精确控制是如何可能的呢？尽管我们熟悉参与这一过程的基因，但我们仍然相对不了解这些基因如何组合成能够实现精确时间控制的电路。群体规模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日益成功的技术，通过该技术可以将个体的 T 细胞现有的工程 T 细胞不具备针对癌症进行重新设计的能力。调节它们的数量——类似于无法控制剂量、副作用的药物。可能会发生与增殖不足或过度增殖有关的情况。为了增强我们对 T 细胞群体扩张的理解，我建议采用工程方法将在 T 细胞中综合构建新的遗传电路，从而控制群体大小促进细胞分裂或死亡的蛋白质将由细胞人工合成。对化学刺激的反应，这些生长和死亡成分将以不同的方式组合起来使用这些系统在细胞群中创建不同的用户可调节行为，我计划确定遗传电路设计与由此产生的种群扩张动态之间的关系收缩。拟议的研究将提供监管要素类型的普遍特征可以产生不同的群体规模动态。其中一些合成电路本身可能是有用的。开发新的癌症 T 细胞疗法的工具。这里揭示的可能揭示控制天然增殖控制线路的设计原则系统。