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MICROFLUIDIC SYSTEM FOR HIGH-THROUGHPUT EVALUATION OF T CELL FUNCTIONALITY WITH H

使用 H 对 T 细胞功能进行高通量评估的微流控系统

基本信息

批准号：
7677480
负责人：
Melissa Lambeth Kemp
金额：
$ 16.35万
依托单位：
GEORGIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7677480
关键词：
Adoptive Transfer Automation Behavior Biochemical Biological Assay Cell Culture Techniques Cell Therapy Cells Cellular Stress Characteristics Clinical Computer Simulation Cytolysis Data Defense Mechanisms Development Devices Engineering Environment Evaluation Feedback Goals Human Immune Immune response In Vitro Length Measurement Measures Medical Technology Microfluidics Mind Modeling Monitor Nature Oncologist Patients Performance Population Production Property Proteins Research Resolution Sampling Specificity System T-Cell Activation T-Cell Immunologic Specificity T-Lymphocyte Technology Temperature Testing Time Translating Tumor Antigens Work anergy base biological adaptation to stress cancer therapy cytokine design exhaustion improved in vivo innovation innovative technologies multidisciplinary neoplastic cell protein activation research study response senescence tool tumor

项目摘要

DESCRIPTION (provided by applicant): Adoptive transfer of T cells is a promising clinical cancer therapy that relies on enhancing the adaptive immune response to target tumor cells in vivo. Widespread application of this therapy, however, has been hindered by the necessary expansion of large populations of T cells for each patient (often selected for tumor antigen specificity) and loss of functionality of the T cells post-transfer. Our long-term objective is to understand how T cell activation is dampened in vivo by the tumor milieu and to be able to evaluate the responsiveness ex vivo-expanded T cells accurately for cancer therapy. Microfluidic chips are ideal for high-throughput parallel experimentation and automation. In addition, microfluidics also provides the relevant length scales (~microns) and unique physical phenomena (e.g. laminar flow) to handle cells. The type of multiplex data that we can obtain from this technology will enable quantitative modeling of T cell activation and better understanding and characterization of anergy. The objective of this R21 project is to engineer a multiplex microfluidic assay to quantify T cell activation on a small population of cells with high temporal resolution. The hypothesis is that capturing the early dynamics of T cell activation of ex vivo expanded clones would improve upon current measures of T cell functionality. The first component of this project is to develop the high-throughput microfluidic system for multiple time-point stimulation and lysis of cells; in parallel, we are to develop biochemical assays to characterize the performance of the system and the cell state. The second component is to perform in vitro characterization of ex vivo expanded T cells for distinguishing anergic versus responsive behavior. The approach is innovative because the technology developed here dramatically increases the capabilities and throughput of existing assays in evaluating T cells for adoptive transfer. Furthermore, this work proposes and tests a new paradigm in T cell evaluation using multiplex quantitative means. The proposed research is significant because it is expected to expand the toolbox of cancer therapy and possibly other related quantitative biosciences and medical technologies.

描述（申请人提供）：T细胞过继性转移是一种很有前途的临床癌症治疗方法，它依赖于增强体内对靶肿瘤细胞的适应性免疫反应。然而，这种疗法的广泛应用一直受到每个患者所需的大量T细胞扩增（通常是为了肿瘤抗原特异性而选择的）和T细胞转移后功能丧失的阻碍。我们的长期目标是了解肿瘤环境如何抑制体内T细胞的活化，并能够准确评估体外扩增T细胞对癌症治疗的反应性。微流控芯片是高通量并行实验和自动化的理想选择。此外，微流体还提供了相关的长度尺度（~微米）和独特的物理现象（如层流）来处理细胞。我们可以从这项技术中获得的多重数据类型将使T细胞活化的定量建模和更好地理解和表征能量。这个R21项目的目标是设计一个多重微流控分析，以高时间分辨率量化T细胞在小细胞群上的激活。其假设是，捕获离体扩增克隆的T细胞激活的早期动态将改善当前对T细胞功能的测量。该项目的第一个组成部分是开发用于多时间点刺激和裂解细胞的高通量微流体系统；同时，我们将开发生化分析来表征系统的性能和细胞状态。第二个组成部分是进行体外扩增T细胞的体外表征，以区分无能和反应行为。该方法具有创新性，因为这里开发的技术大大提高了评估T细胞过继转移的现有检测方法的能力和吞吐量。此外，这项工作提出并测试了使用多重定量手段进行T细胞评估的新范式。这项拟议的研究意义重大，因为它有望扩大癌症治疗的工具箱，并可能扩大其他相关的定量生物科学和医学技术。