Core B: Metabolomics/Genomics Core

总结 该计划项目的中心宗旨是，综合应激反应（ISR）发挥着关键作用 通过其参与MYC依赖性和低氧依赖性肿瘤进展的能力， 调节昼夜节律、代谢和免疫功能的关键途径， 肿瘤细胞的存活和生长。 非细胞自主应激（缺氧和营养剥夺）与细胞外基质的结合， MYC转化导致快速增殖细胞的生物能量需求增加 需要重新布线的代谢向更高的糖酵解速率（瓦尔堡效应），以及更多的 减少环境以对抗由仍在进行的呼吸产生的增加的ROS。初步 来自所有3个项目的数据都涉及影响代谢和氧化还原状态的过程：MYC活化， 生物钟失调和T细胞活化都与中心碳的变化有关， 新陈代谢.因此，在此类代谢物分析中提供“交钥匙”服务的核心将 对于细胞和动物模型的关键发现的有效和快速进展至关重要。 与此同时，Myc和ATF 4（所有3个项目的关键组分）都是转录因子， 通过广泛的网络和合作伙伴发挥他们的活动，有必要分析基因 表达谱，包括mRNA和miRNA。最后，项目2将严重依赖于性能 Myc和ATF 4在不同环境下的Chip-Seq实验，产生了数据丰富的结果， 需要专业的生物信息学工具来解析重要数据。根据目标1，核心将分析 代谢产物，包括糖酵解产物、氨基酸和肿瘤和正常组织的ATP水平 和细胞的信息。根据目标2，核心将分析基因水平， 表达，包括来自正常和肿瘤组织和细胞的mRNA、miRNA和非编码RNA，和 进行生物信息学分析、本体分析和数据可视化。 此外，代谢组学和基因组学（生物信息学）的整合工作， 我们活动的核心和协调将使基因组和 代谢组学数据作为特定假设验证的附加水平（例如，microRNA X抑制 酶Y的合成产生，这将导致代谢物Z水平的变化）。成功 这些目标的实施将促进提高业务效率和一体化 三个主要计划项目之间的思想和概念。

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.