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.
One of the goals Core B (Metabolomics-Genomics) will be to provide analysis for the levels of specific metabolites and the bioenergetics status of cells and tissues within cells are analyzed. The other goal will be to provide information on the levels of specific gene products which regulate these processes. This information is crucial for the successful completion of the Aims in all three supported projects.
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