Enabling NF-kB Signal Transduction Studies in Primary Multiple Myeloma Cells

在原发性多发性骨髓瘤细胞中进行 NF-kB 信号转导研究

基本信息

批准号：
8660040
负责人：
David J Beebe
金额：
$ 27.26万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-21 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8660040
关键词：
Address Advanced Development Antineoplastic Agents Area Biological Biological Assay Biological Markers Biology Biomedical Engineering Biopsy Specimen Blood Bone Marrow Bone Marrow Cells Bortezomib Cancer Biology Cancer Patient Cell Count Cell Culture Techniques Cell Death Cells Cessation of life Classification Coculture Techniques Development Devices Drug Industry Drug Targeting Drug resistance Future Generations Genes Genomics Human Knowledge Laboratories Life Malignant Neoplasms Manuals Measures Mediating Medicine Methodology Methods Microfluidics Multiple Myeloma NF-kappa B Pathology Pathway interactions Patient Care Patients Pharmaceutical Preparations Pharmacologic Substance Proteasome Inhibitor Proteomics Pump Regulation Research Research Infrastructure Resistance Role Sample Size Sampling Side Signal Transduction Solid Source Specimen Stromal Cells System Techniques Technology Translational Research anticancer research base cancer cell cancer type cell type design flexibility high throughput analysis high throughput technology improved innovation insight killings novel prototype response tumor tumor microenvironment

项目摘要

DESCRIPTION (provided by applicant): In contrast to highly sensitive genomic and proteomic methods that primarily evaluate the state of cancer specimens, functional analyses of primary patient samples to assess their biological responses to various experimental conditions are difficult because of the often limited number of live primary cells that can be obtained from patient biopsy samples. Thus, overcoming this technical barrier has the potential to transform our ability to significantly increase translational cancer research approaches. By combining expertise in, cancer cell signaling, bioengineering, and primary patient care, the Miyamoto-Beebe-Callander team proposes to improve our ability to functionally analyze NF-kB signal transduction responses in primary patient multiple myeloma (MM) samples. Specifically, we propose to develop innovative microchannel culture devices and implement functional studies to investigate a dogma-challenging NF-kB-survival pathway in MM. We have already developed prototype culture devices that increase our ability to analyze primary MM cells. These microculture systems also provide the flexibility to study components of the tumor microenvironment, such as tumor-supporting bone marrow stromal cells (BMSCs). Under Aim 1 we will dissect drug resistance-inducing NF-kB signaling mechanisms in primary MM cells using the first generation microscale cell culture chambers (MCCCs). We also aim to reveal patient individualized information by co- culturing MM cells and BMSCs derived from the same patients, a paradigm shift from the conventional experimental setup where patient sources of MM and BMSCs are randomly mixed. Under Aim 2 we will further improve functional micro-scale assays with additional functionalities and with even smaller cell numbers per condition, thus greatly expanding the scope of translational research in MM. The micro-culture technology proposed has the potential to rapidly change the methods used for investigating signal transduction studies, including NF-kB, in MM and other blood and possibly solid cancer types.

描述（由申请人提供）：与主要评估癌症样本状态的高度敏感的基因组和蛋白质组学方法相比，对主要患者样本进行功能分析以评估其对各种实验条件的生物反应是困难的，因为活体数量通常有限可以从患者活检样本中获得的原代细胞。因此，克服这一技术障碍有可能改变我们显着增加转化癌症研究方法的能力。通过结合癌细胞信号传导、生物工程和初级患者护理方面的专业知识，Miyamoto-Beebe-Callander 团队建议提高我们对原发性多发性骨髓瘤 (MM) 患者样本中 NF-kB 信号转导反应进行功能分析的能力。具体来说，我们建议开发创新的微通道培养装置并实施功能研究，以研究 MM 中挑战教条的 NF-kB 生存途径。我们已经开发了原型培养装置，可以提高我们分析原代 MM 细胞的能力。这些微培养系统还提供了研究肿瘤微环境成分的灵活性，例如肿瘤支持骨髓基质细胞（BMSC）。在目标 1 下，我们将使用第一代微型细胞培养室 (MCCC) 剖析原代 MM 细胞中耐药性诱导的 NF-kB 信号传导机制。我们还旨在通过共培养来自同一患者的 MM 细胞和 BMSC 来揭示患者个体化信息，这与传统实验设置（其中患者来源的 MM 和 BMSC 随机混合）的范式转变。在目标 2 下，我们将进一步改进功能性微尺度测定，提供额外的功能以及每种条件下更小的细胞数量，从而极大地扩大 MM 转化研究的范围。所提出的微培养技术有可能迅速改变用于调查信号转导研究的方法，包括 MM 和其他血液癌以及可能的实体癌类型中的 NF-kB。