Core B: Metabolomics/Genomics Core

摘要 该项目的中心原则是综合应激反应(ISR)起着举足轻重的作用 在介导MYC依赖和缺氧依赖的肿瘤进展中的作用 并调节参与昼夜节律、代谢和免疫功能的关键途径，从而促进 肿瘤细胞的存活和生长。 非细胞自主应激(缺氧和营养缺乏)与 MYC转化对快速增殖细胞的生物能量学需求增加 有必要重新连接新陈代谢以获得更高的糖酵解率(Warburg效应)以及更多 减少环境以对抗仍在进行的呼吸产生的增加的ROS。初步 所有三个项目的数据都影响了影响代谢和氧化还原状态的过程：MYC激活， 生物钟失调和T细胞激活都与中枢碳的变化有关 新陈代谢。因此，在这些代谢物的分析中提供“交钥匙”服务的核心将 对于有效和快速地推进细胞和动物模型的关键发现至关重要。 同时，Myc和ATF4(所有3个项目的关键成分)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，需要对基因进行分析 表达谱，包括mRNAs和miRNAs。最后，项目2将严重依赖于性能 在不同的环境下对Myc和ATF4进行CHIP-SEQ实验，生成丰富的数据结果 需要专业的生物信息学工具来解析重要数据。在目标1下，核心将分析 来自肿瘤和正常组织的代谢物，包括糖酵解产物、氨基酸和ATP水平 和细胞使用核磁共振和质谱学。在目标2下，核心将分析基因水平 正常和肿瘤组织和细胞的表达，包括mRNA、miRNA和非编码RNA，以及 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)的整合工作在一个单一的 我们活动的核心和协调将使基因组和 代谢数据作为特定假设的额外验证水平(例如，microRNA X抑制 应导致代谢物Z水平变化的酶Y的合成)。成功 这些目标的实现将成为提高业务效率和一体化的催化剂 三个主要计划项目之间的想法和概念。

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.