Core B: Metabolomics/Genomics Core

核心 B：代谢组学/基因组学核心

• 批准号: 10247667
• 负责人: Aalim M Weljie
• 金额: $ 13.13万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10247667
• 关键词: Affect; Amino Acids; Animal Model; Bioenergetics; Bioinformatics; Carbon; Cell Survival; Cells; ChIP-seq; Coupled; Data; Environment; Enzymes; Funding; Gene Expression; Gene Expression Profiling; Genomics; Glycolysis; Goals; Health Services Research; Hypoxia; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Messenger RNA; Metabolic; Metabolism; MicroRNAs; Normal Cell; Normal tissue morphology; Ontology; Outcome; Oxidation-Reduction; Pathway interactions; Performance; Play; Process; Production; Proliferating; Regulation; Resource Sharing; Respiration; Role; Services; Stress; T-Cell Activation; Time; Tissues; Translations; Tumor Tissue; Untranslated RNA; Validation; Warburg Effect; bioinformatics tool; biological adaptation to stress; catalyst; cell growth; circadian; circadian pacemaker; combat; data visualization; experimental study; gene product; immune function; innovation; interest; metabolomics; neoplastic cell; nutrient deprivation; programs; transcription factor; tumor microenvironment; tumor progression

Summary The central tenet of this Program Project is that the Integrated Stress Response (ISR) plays a pivotal role in mediating MYC-dependent and hypoxia-dependent tumor progression through its capacity to engage and regulate key pathways involved in circadian, metabolic and immune functions thereby facilitating tumor cell survival and growth. The combination of non-cell autonomous stresses (hypoxia, and nutrient deprivation) coupled with the increased bioenergetics demands of a rapidly proliferating cell imposed by MYC transformation necessitate rewiring of metabolism towards a higher glycolytic rate (Warburg effect) as well as a more reducing environment to combat increased ROS produced by the still ongoing respiration. Preliminary data form all 3 projects impinge upon processes which affect metabolic and redox status: MYC activation, circadian clock dysregulation and T cell activation have all been implicated in changes in central carbon metabolism. Therefore, a Core which provides “turn-key” services in the analysis of such metabolites will be crucial for the efficient and rapid advancement of key findings with cellular as well as animal models. At the same time, the fact that Myc and ATF4 (key components in all 3 projects) are transcription factors exerting their activity through extensive networks and partners, necessitates the analysis of gene expression profiles, including mRNAs and miRNAs. Finally, project 2 will rely heavily on the performance of ChiP-Seq experiments for Myc and ATF4 in different settings, generating data-rich outcomes which require expert bioinformatics tools to parse important data. Under Aim 1, the Core will analyze levels of metabolites, including products of glycolysis, amino acids and ATP levels from tumor and normal tissues and cells using NMR and mass spectrometry. Under Aim 2, the Core will analyze levels of gene expression including mRNA, miRNA and non-coding RNA from normal and tumor tissues and cells, and perform bioinformatics analysis, ontology analysis and data visualization. Moreover, the integration of the Metabolomics and Genomics (Bioinformatics) efforts under a single Core and coordination of our activities would enable direct comparisons between genomic and metabolomic data as additional level of validation of specific hypotheses (e.g., microRNA X represses synthesis of enzyme Y production which should result in changes in levels of metabolite Z). Successful implementation of these Aims will serve as a catalyst for increased operational efficiency and integration of ideas and concepts among the three main Program Projects.

概括 该计划项目的核心宗旨是综合压力响应（ISR）起着关键作用 通过参与能力介导MYC依赖性和缺氧依赖性肿瘤的进展 并调节昼夜节律，代谢和免疫功能的关键途径，从而支持 肿瘤细胞的存活和生长。 非细胞自主应力（缺氧和营养剥夺）的结合与 MYC转化施加的快速增殖细胞的生物能量需求增加 需要将代谢重新布线换向更高的糖酵解速率（Warburg效应）以及更多 还原环境以增加仍在持续的呼吸产生的ROS增加。初步的 数据表格所有3个项目都影响了影响代谢和氧化还原状态的过程：MYC激活， 昼夜节律时钟失调和T细胞激活都暗示了中央碳的变化 代谢。因此，在分析此类代谢物中提供“旋转”服务的核心将 对于通过细胞和动物模型的关键发现的有效和快速发展至关重要。 同时，MYC和ATF4（所有3个项目中的关键组成部分）是转录因素的事实 通过广泛的网络和合作伙伴进行活动，必要基因分析 表达谱，包括mRNA和miRNA。最后，项目2将严重依赖性能 在不同的设置中用于MYC和ATF4的芯片seq实验，生成数据丰富的结果 需要专家生物信息学工具来解析重要数据。在AIM 1下，核心将分析 代谢产物，包括糖酵解的产物，氨基酸和来自肿瘤和正常组织的ATP水平 使用NMR和质谱法。在AIM 2下，核心将分析基因水平 表达包括正常组织和细胞的mRNA，miRNA和非编码RNA，以及 执行生物信息学分析，本体分析和数据可视化。 此外，在一个单一的工作中的代谢组学和基因组学（生物信息学）的整合 我们的活动的核心和协调将使基因组和 代谢组数据作为特定假设的额外验证级别（例如MicroRNA X表示 酶产生的合成应导致代谢产物z的水平变化。成功的 这些目标的实施将成为提高运营效率和集成的催化剂 三个主要计划项目中的思想和概念。