Systems biology of glutamine utilization in melanoma

黑色素瘤中谷氨酰胺利用的系统生物学

基本信息

批准号：
8624405
负责人：
Jeffrey W Smith
金额：
$ 25.45万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8624405
关键词：
Accounting Address American Cancer Society BRAF gene Biological Assay Biological Markers Carbon Cell Line Cells Cellular biology Cessation of life Citric Acid Cycle Development Diagnostic Disease Drug Targeting Energy-Generating Resources Engineering Enzymes Gene Expression Gene Silencing Gene Targeting Genetic Suppression Glutamates Glutaminase Glutamine Growth Health Human In Vitro Malignant Neoplasms Medical Melanoma Cell Metabolic Metabolic Pathway Metabolism Modeling Monitor Mus Mutate Mutation Neoplasm Metastasis Nitrogen Oncogenes Oncogenic Output Pathway interactions Patients Physiological Physiology Primary Neoplasm Production Research Research Personnel Resistance Role Side Signal Pathway Skin Cancer Source Staging Systems Biology Techniques Testing Therapeutic Therapeutic Agents Validation Xenograft Model Xenograft procedure addiction base cell type deprivation feeding in vivo insight interest melanoma metabolomics mouse model new therapeutic target novel novel therapeutics overexpression stable isotope therapeutic development therapeutic target translational study tumor tumor growth tumor progression tumor xenograft tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Development of new therapies against melanoma, a nearly incurable disease if allowed to progress to the deadly metastatic stage, is a well-recognized medical need. As in all other cancers, tumorigenesis and tumor progression in melanoma is accompanied by substantial rewiring of central carbon metabolism opening unexplored opportunities for diagnostics and treatment. Recent studies of the investigators of this application implicated a substantially enhanced utilization of glutamine as an essential anaplerotic source of carbon and energy and a potential therapeutic target in human melanoma cell lines. The preliminary results of these studies led to the specific hypothesis about the critial importance of the cataplerotic exit of glutamine- originating carbon units from the tricarboxylic acid cycle, which may provide unique targeting opportunities. The proposed studies will address this hypothesis using an established integrative approach, which combines multifaceted metabolic analyses, including stable-isotope tracing, with genetic suppression of selected target enzymes over a panel of representative human melanoma lines followed by testing and validation of main finding in mouse xenograft models. In addition to gaining fundamental mechanistic insights, anticipated deliverables of the project would include validated biomarkers (signature metabolites and/or fluxes) and potential target enzymes. The proposed research plan includes two major specific aims featuring in vitro and in vivo studies: (I) to elucidate mechanisms and identify potential diagnostic and therapeutic targets involved in the key aspects of glutamine metabolism in a range of melanoma cell lines by a synergistic combination of techniques including targeted metabolomics, physiology and cell biology; (II) to validate the key aspects of glutamine metabolism, biomarkers and tentatively identified targets in the xenograft mouse models of primary melanoma tumors and metastases. If successfully accomplished, this project would provide a strong starting point for advanced translational studies and therapeutic developments

描述（由申请人提供）：针对黑色素瘤的新疗法开发，如果允许进入致命的转移阶段，几乎无法治愈的疾病，是公认的医疗需求。与所有其他癌症一样，黑色素瘤中的肿瘤发生和肿瘤进展伴随着中央碳代谢的大量重新布线，为诊断和治疗打开了未开发的机会。对该应用的研究人员的最新研究表明，谷氨酰胺作为碳和能量的必不可少来源的利用率大大提高了，并且在人类黑色素瘤细胞系中的潜在治疗靶点。这些研究的初步结果导致了有关谷氨酸产生碳单元的批评性重要性的具体假设，从三羧酸周期中，这可能会提供独特的靶向机会。拟议的研究将使用已建立的综合方法来解决这一假设，该方法结合了多方面的代谢分析，包括稳定的异位示踪，以及对所选靶酶的遗传抑制在代表性的人黑色素瘤线上，然后通过测试小鼠Xenogrograft模型中的主要发现和验证。除了获得基本的机理见解外，该项目的预期可交付成果还包括经过验证的生物标志物（签名代谢物和/或通量）和潜在的靶酶。拟议的研究计划包括两个主要的特定目标，其中包括体外和体内研究：（i）阐明机制并确定在黑色素瘤细胞系中通过包括靶向技术的技术组合在内的黑色素瘤细胞系中谷氨酰胺代谢的关键方面涉及的潜在诊断和治疗靶标的，包括靶向的技术，生理，生理学和生理学，生理学，生理学和生理学，生理学和生理学；（ii）验证谷氨酰胺代谢的关键方面，生物标志物和暂定鉴定的靶标在原发性黑色素瘤肿瘤和转移酶的异种移植小鼠模型中。如果成功完成，该项目将为高级翻译研究和治疗发展提供强大的起点