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很大程度上受到细胞外信号（例如生长因子和炎症细胞因子）的影响。这些信号激活的细胞内信号通路通常会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，多个信号传导途径可能被激活，导致被称为“串扰”的复杂相互作用，从而难以识别关键的致癌途径或提出靶向治疗。因此，需要对癌症信号传导有一个全面的、全系统的看法。 实现癌细胞动态信号行为的真正系统分析的一个重要障碍是缺乏系统、有效和可重复地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装置。这些设备包含数十个可以填充细胞的微型室。使用传统的免疫细胞化学方法可以独立刺激和监测每个室中的细胞的不同信号传导事件。除了可以在单个设备中进行大量并行测量之外，微流体还可以精确控制实验条件，提高再现性并使定量更加准确。我们现有的原型已经过所有主要所需功能的测试，并为我们的技术方法提供了原理证明。 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，对不同癌细胞中的细胞信号传导特征进行分类。该应用的主要重点是增加设备和支持设备的尺寸和容量，并通过对癌细胞系和恶性黑色素瘤活检细胞中的信号传导进行试点筛选来展示其功能。这些试点筛选可能会揭示用于癌症诊断的新的基于信号转导的标记，并建议最佳的化疗靶点。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，该设备的使用可能会转化为临床实验室，特别是它能够直接在患者细胞上进行多项实验。我们设想临床医生最终将能够将该设备用于个性化治疗，例如，通过使用小活检来筛选标记药物敏感性的各种信号特征，或直接测试化疗药物的疗效。