Microfluidic Devices for Studying Cancer Signal Transduction

用于研究癌症信号转导的微流体装置

• 批准号: 7502499
• 负责人: Andre Levchenko
• 金额: $ 23.7万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7502499
• 关键词: Antibodies; Behavior; Biological Assay; Biological Markers; Biopsy; Cancer cell line; Cataloging; Catalogs; Cell Line; Cells; Classification; Clinical; Complex; Condition; Cues; Data Set; Detection; Devices; Diagnosis; Disease Marker; Drug Delivery Systems; Epigenetic Process; Equipment; Event; Gene Expression; Genetic; Genotype; Growth Factor; Heterogeneity; Immunohistochemistry; Inflammation; Inflammatory; Inflammatory Response; Laboratories; Link; Malignant Neoplasms; Measurement; Measures; Methods; Microfluidic Microchips; Mining; Molecular Analysis; Molecular Profiling; Monitor; Numbers; Output; Pathway interactions; Patients; Personal Satisfaction; Pharmaceutical Preparations; Phenotype; Phosphorylation; Predisposition; Procedures; Property; Reagent; Reproducibility; Research; Sampling; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Staining method; Stains; System; Technology; Testing; Therapeutic; Translating; Translations; anticancer research; base; cancer cell; cancer diagnosis; chemotherapeutic agent; combinatorial; cytokine; extracellular; immunocytochemistry; improved; melanocyte; melanoma; neoplastic; novel; prototype; research study; response; size; tool

DESCRIPTION (provided by applicant): The emergence and progression of various cancers is heavily influenced by extracellular cues such as growth factors and inflammatory cytokines. The intracellular signaling pathways activated by these cues often have altered behavior and new dynamic properties, leading to neoplastic behavior. Furthermore, in a given cell, multiple signaling pathways may be activated leading to complex interactions known as 'cross-talk' and making it difficult to identify key carcinogenic pathways, or to propose targeted treatment. Therefore, a comprehensive, systems-wide view of cancer signaling is required. An important barrier to achieving a truly systemic analysis of dynamic signaling behavior in cancer cells is the lack of a tool to systematically, efficiently, and reproducibly measure the immediate signaling outputs. Here we propose to develop and enhance novel microfluidic devices that can overcome this barrier. The devices contain dozens of miniature chambers which can be filled with cells. Cells in each chamber can be independently stimulated and monitored for a distinct signaling event using conventional immunocytochemistry methods. In addition to the large number of parallel measurements that can be made in a single device, microfluidics offers precise control over experimental conditions, enhancing reproducibility and making quantification more accurate. Our existing prototypes have been tested for all major required functions and provide proof-of-principle of our technological approach. We propose to further develop the existing prototypes to enable very high-throughput experiments cataloging cell signaling signatures in diverse cancer cells. The main focus of this application is to increase the size and capacity of the device and supporting equipment, and demonstrate its functionality through a pilot screen of signaling in cancer cell lines and cells from malignant melanoma biopsies. These pilot screens may reveal new signal transduction-based markers for cancer diagnosis and suggest optimal chemotherapeutic targets. We anticipate that the device will become a powerful research tool to study signal transduction. Furthermore, the use of the device could potentially translate to clinical laboratories, specifically in its ability to perform multiple experiments directly on a patient's cells. We envision clinicians will eventually be able to use the device in personalized therapy, for example, by using a small biopsy to screen for various signaling features that mark drug susceptibility or by directly testing the efficacy of chemotherapeutic agents.

描述（由申请人提供）：各种癌症的出现和进展受到细胞外提示，例如生长因子和炎症细胞因子。这些提示激活的细胞内信号通路通常具有改变行为和新的动态特性，从而导致肿瘤行为。此外，在给定的细胞中，可以激活多个信号通路，从而导致复杂的相互作用称为“交叉对话”，并且难以识别关键的致癌途径或提出靶向治疗。因此，需要对癌症信号的全面视图。 实现癌细胞中动态信号行为的真正系统性分析的重要障碍是缺乏系统，有效和可重复测量即时信号输出的工具。在这里，我们建议开发和增强可以克服这一障碍的新型微流体设备。这些设备包含数十个微型室，可以填充细胞。可以使用常规的免疫细胞化学方法对每个腔室中的细胞进行独立刺激和监测，以进行独特的信号传导事件。除了可以在单个设备中进行的大量并行测量值之外，微流体还可以精确控制实验条件，增强了可重复性并使量化更准确。我们现有的原型已针对所有主要必需功能进行了测试，并提供了我们技术方法的原理证明。 我们建议进一步开发现有的原型，以实现非常高通量的实验，以分解各种癌细胞中的细胞信号传导特征。该应用的主要重点是增加设备的尺寸和容量和支撑设备，并通过癌细胞系中的信号传导和来自恶性黑色素瘤活检的细胞的信号传导来证明其功能。这些试点筛选可能揭示了用于癌症诊断的新的基于信号转导的标记，并提出了最佳的化学治疗靶标。我们预计该设备将成为研究信号转导的强大研究工具。此外，该设备的使用可能可能转化为临床实验室，特别是其直接在患者细胞上进行多个实验的能力。我们设想临床医生最终将能够在个性化治疗中使用该设备，例如，使用小型活检来筛选标记药物敏感性或直接测试化学治疗剂的功效的各种信号传导特征。