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High-Throughput Screening Under Static or Dynamic Hypoxia

静态或动态缺氧下的高通量筛选

基本信息

批准号：
9315116
负责人：
MICHAEL GAMCSIK
金额：
$ 21.44万
依托单位：
NORTH CAROLINA STATE UNIVERSITY RALEIGH
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：
2016-07-13 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9315116
关键词：
Address Adoption Air Animal Model Antineoplastic Agents Area Behavior Biological Biological Assay Biological Markers Breast Cancer Patient Cancer cell line Carbon Dioxide Cell Culture Techniques Cell Survival Cell physiology Cells Chronic Clinical Culture Media Cultured Cells Custom Data Devices Dimensions Dose Growth Human Human Cell Line Humidifier Hypoxia In Vitro Incubators Industry Standard Investigation Laboratories Link Malignant Neoplasms Mammalian Cell Measures Metabolism Methods Molecular Molecular Analysis Monitor New Agents Normal tissue morphology Oxygen Partial Pressure Patient-Focused Outcomes Pattern Pharmaceutical Preparations Physiological Process Prognostic Marker Protocols documentation Public Health Reaction Time Reader System Technology Time Tissues Tumor Tissue Venous biomarker development biomarker discovery biomarker identification cancer initiation cancer therapy cell growth clinically relevant culture plates design driving force drug discovery experience flasks genetic signature high standard high throughput screening improved in vitro Model in vivo interest laboratory experiment microdevice novel oncology oxygen transport planetary Atmosphere prognostic protein expression purge response response biomarker screening tissue culture tool tumor tumor microenvironment tumor progression

项目摘要

ABSTRACT The presence of hypoxia in a many human tumors is a widely observed negative prognostic indicator. Laboratory experiments in animal models and in vitro systems are consistent with the clinical observations showing that hypoxia is a major driving force in cancer progression. Since hypoxia is difficult to control and measure in animal models, in vitro approaches offer the best opportunity for detailed molecular analysis of the influence of oxygen on cancer initiation, progression and analysis. However, clinical tumors display a range of oxygen levels with some regions that are chronically hypoxic whereas other regions experience time- dependent changes, i.e. cycling hypoxia. This further complicates systematic analysis of hypoxic responses as there are literally an infinite number of static and cycling hypoxia patterns that can be probed. To date, studies of cycling hypoxia usually are limited to probing a single, arbitrarily chosen cycling pattern that may not be clinically relevant. In order to facilitate screening of both chronic and dynamic changes in hypoxia, we propose to develop a technology that can deliver a range of hypoxia levels, either static or cycling, to each row of a standard multiwell tissue culture plate. This allows monitoring of molecular adaptation, cell growth and drug response under a range of oxygen concentrations simultaneously. The initial studies will demonstrate the technology on a standard 96-well plate format that is compatible with current multichannel pipettors, plate readers and laboratory protocols that allows immediate adoption to any oncology laboratory. The same principles can be used in any multiwell plate to aid in assessing the effect of oxygen on cell growth and viability, tumor progression, biomarker identification and therapy response. There is no current technology that allows these types of investigations in a standard high-throughput format. This technology addresses at least two areas of interest in the RFA as it will aid in (i) the elucidation of the basic mechanisms underlying cancer initiation and progression and (ii) facilitate/accelerate the processes of drug discovery.

抽象的许多人类肿瘤中缺氧的存在是一种广泛观察到的负面预后指标。动物模型和体外系统的实验室实验与临床观察结果一致表明缺氧是癌症进展的主要驱动力。由于缺氧难以控制在动物模型中测量，体外方法为详细分子分析提供了最佳机会氧气对癌症发生、进展和分析的影响。然而，临床肿瘤表现出某些区域长期缺氧，而其他区域则经历时间-氧气水平范围依赖性变化，即循环缺氧。这使得缺氧反应的系统分析进一步复杂化因为实际上可以探测到无数的静态和循环缺氧模式。迄今为止，对循环缺氧的研究通常仅限于探索单一的、任意选择的循环模式，该模式可能会导致缺氧。没有临床相关性。为了便于筛查缺氧的慢性和动态变化，我们提议开发一种技术，可以为每个人提供一系列的缺氧水平（静态或循环）一排标准多孔组织培养板。这可以监测分子适应、细胞生长同时在一定范围的氧气浓度下进行药物反应。初步研究将在与当前多通道兼容的标准 96 孔板格式上展示该技术移液器、读板器和实验室协议可立即被任何肿瘤实验室采用。相同的原理可用于任何多孔板，以帮助评估氧气对细胞生长的影响以及活力、肿瘤进展、生物标志物识别和治疗反应。没有电流允许以标准高通量格式进行此类研究的技术。这项技术解决 RFA 中至少两个感兴趣的领域，因为它将有助于 (i) 阐明基本机制潜在的癌症发生和进展以及（ii）促进/加速药物发现的过程。