New Model of the Tumor Microenvironment

肿瘤微环境的新模型

基本信息

批准号：
6810402
负责人：
James P Freyer
金额：
$ 27.05万
依托单位：
UNIVERSITY OF CALIF-LOS ALAMOS NAT LAB
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-17 至 2006-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The over-all goal of this two-year project will be to develop and refine a novel three-dimensional tumor model in which we can measure spatial distributions of microenvironmental parameters and directly compare these with alterations in cellular physiology and functional genomics. We propose three Specific Aims to develop and initially validate this new experimental model system. The first Aim is to develop a novel three dimensional cell culture chamber for spatially-resolved cell physiology, gene and protein expression. This chamber will provide steady-state gradients of microenvironmental factors that are spatially correlated with gradients in cellular physiology, metabolism and gene/protein expression. The second Aim is to develop NMR 1-D imaging methods for oxygen, pH, glucose/lactate and cell density/flow. These methods will provide 1-D maps of concentration gradients that are spatially correlated with the corresponding gradients in cellular parameters. The third Aim will be to develop and validate a mass transport model for fitting the NMR concentration profiles in order to obtain cellular metabolic parameters. The aims are highly interactive: improvements in spatial resolution of the NMR imaging methods will be coupled to development of a more tissue-like system for cell culture, and visa versa. The data from each iteration of the system will be analyzed using the mass transport model, which will, in turn, be refined based on the results obtained. This will be the first 3-D cell culture system available for measuring the effects on tumor cells of exposure to known combinations of metabolite and catabolite gradients. Although the aims of this two-year application are primarily to develop, validate and refine the new model system, we produce preliminary data demonstrating the usefulness of this system for our ongoing projects in studying the tumor microenvironment. We anticipate application of this new system to answer fundamental questions about the regulation of cellular metabolism, proliferation, physiology, and gene/protein expression under multi-component microenvironmental stress, which closely mimics the situation in tumors. This system will be useful in a wide variety of other basic and applied cancer research areas, including drug development, radiobiology, and non-invasive diagnosis. The new tumor model system should also serve as an excellent platform for improving biomedical imaging, particularly NMR microimaging. The system is also potentially very useful for applied research on cell culture systems for biomaterial production and artificial organs. Finally, this system should prove useful for investigating the regulation of metabolism and physiology in microbial systems, a current area of intense interest.

描述（由申请人提供）：这个为期两年的项目的总体目标是开发和完善一种新型三维肿瘤模型，在该模型中我们可以测量微环境参数的空间分布，并直接将其与细胞生理学的变化进行比较和功能基因组学。我们提出了三个具体目标来开发并初步验证这个新的实验模型系统。第一个目标是开发一种新型三维细胞培养室，用于空间分辨细胞生理学、基因和蛋白质表达。该室将提供微环境因素的稳态梯度，这些因素与细胞生理学、代谢和基因/蛋白质表达的梯度在空间上相关。第二个目标是开发用于氧、pH、葡萄糖/乳酸和细胞密度/流量的 NMR 一维成像方法。这些方法将提供与细胞参数中相应梯度空间相关的一维浓度梯度图。第三个目标是开发和验证质量传递模型，用于拟合 NMR 浓度分布，以获得细胞代谢参数。这些目标是高度互动的：核磁共振成像方法空间分辨率的提高将与开发更类似于组织的细胞培养系统相结合，反之亦然。系统每次迭代的数据将使用质量传输模型进行分析，进而根据获得的结果进行细化。这将是第一个可用于测量暴露于已知的代谢物和分解代谢物梯度组合对肿瘤细胞的影响的3D细胞培养系统。尽管这个为期两年的应用的目的主要是开发、验证和完善新模型系统，但我们产生的初步数据证明了该系统对于我们正在进行的肿瘤微环境研究项目的有用性。我们期望应用这个新系统来回答有关多成分微环境应激下细胞代谢、增殖、生理学和基因/蛋白质表达调节的基本问题，这与肿瘤的情况非常相似。该系统将广泛用于其他基础和应用癌症研究领域，包括药物开发、放射生物学和非侵入性诊断。新的肿瘤模型系统还应该成为改善生物医学成像，特别是核磁共振显微成像的优秀平台。该系统对于生物材料生产和人造器官的细胞培养系统的应用研究也可能非常有用。最后，该系统对于研究微生物系统的代谢和生理学调节是有用的，这是当前人们强烈关注的领域。