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Mass Spectrometry Methods for Probing Metabolic Dynamics in Normal & Cancer Cells

探测正常代谢动态的质谱方法

基本信息

批准号：
7432649
负责人：
JOSHUA D RABINOWITZ
金额：
$ 21.63万
依托单位：
PRINCETON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-18 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7432649
关键词：
Advanced Malignant Neoplasm Amino Acids Anabolism Antineoplastic Agents Arts Bacteria Benchmarking Biochemical Pathway Breast Cancer Cell Cancerous Carbon Cells Characteristics Condition Data Data Set Databases Detection Development Dihydrofolate Reductase Electrospray Ionization Fibroblasts Fluorouracil Glucose Glutamine Glycolysis Goals Human Isotope Labeling Kinetics Knowledge Label Lipids Liquid Chromatography Lung Malignant Neoplasms Maps Mass Chromatography Mass Spectrum Analysis Measurement Measures Metabolic Metabolism Methodology Methods Methotrexate Microbe Monitor Neoplasm Metastasis Normal Cell Nucleotide Biosynthesis Nucleotides Numbers Nutrient Pattern Pentosephosphate Pathway Pharmaceutical Preparations Plague Procedures Reaction Resistance Specificity Spectrometry Stable Isotope Labeling Systems Biology Technology Thymidine Thymidylate Synthase Toxic effect Tracer Treatment Protocols Yeasts anticancer research base bone cancer cell cancer therapy chemotherapeutic agent data integration design fibrosarcoma improved inhibitor/antagonist insight killings lipid biosynthesis mass spectrometer metabolomics neoplastic cell novel novel strategies nucleotide metabolism penis foreskin response solvent extraction synovial sarcoma tissue tropism tool tumor

项目摘要

DESCRIPTION (provided by applicant): Many of the most clinically important chemotherapeutic agents inhibit the metabolism of tumor cells. Our overarching goal is to develop a complete and quantitative understanding of the metabolic differences between normal and cancer cells, and to use this knowledge to guide the rational design of novel anticancer regimens. To achieve this goal, we are developing methods that apply state-of-the-art liquid chromatography- electrospray ionization-triple quadrupole mass spectrometry technology to probe cellular metabolism in a dynamic, quantitative, and comprehensive manner. To date, we have succeeded in developing methods for measuring metabolite concentrations and fluxes from several microbes. Here we propose to extend these methods to enable reliable measurement of metabolite concentrations and fluxes in normal and cancer cells. Specifically, we aim to enable quantitation of the concentrations of at least 150 different known, structurally-defined intracellular metabolites. We also aim to measure, using isotopic tracers, the fluxes through central carbon, lipid, amino acid, and nucleotide metabolism. We will apply the analytical technology that we develop to map major metabolic differences between normal and cancer cells and to study the dynamic response of these cells to treatment with anti-metabolite anticancer drugs. The methods developed here will have long-term value for understanding the mechanism of action (and toxicity) of anti-metabolite anticancer drugs, for characterizing the metabolic differences between drug-responsive and resistant cancer cells, and for suggesting new approaches to inhibiting metabolism that will specifically kill cancer cells.

描述（由申请人提供）：许多临床上最重要的化疗药物抑制肿瘤细胞的代谢。我们的首要目标是对正常细胞和癌细胞之间的代谢差异有一个完整和定量的了解，并利用这些知识来指导新型抗癌方案的合理设计。为了实现这一目标，我们正在开发应用最先进的液相色谱-电喷雾电离-三重四极杆质谱技术来动态、定量、全面地探测细胞代谢的方法。迄今为止，我们已经成功开发了测量多种微生物代谢物浓度和通量的方法。在这里，我们建议扩展这些方法，以便能够可靠地测量正常细胞和癌细胞中的代谢物浓度和通量。具体来说，我们的目标是能够对至少 150 种不同的已知、结构明确的细胞内代谢物的浓度进行定量。我们还旨在使用同位素示踪剂测量中心碳、脂质、氨基酸和核苷酸代谢的通量。我们将应用我们开发的分析技术来绘制正常细胞和癌细胞之间的主要代谢差异，并研究这些细胞对抗代谢抗癌药物治疗的动态反应。这里开发的方法对于了解抗代谢抗癌药物的作用（和毒性）机制、表征药物反应性和耐药性癌细胞之间的代谢差异以及提出抑制代谢以特异性杀死癌细胞的新方法具有长期价值。