The Technology Core will will support the aims of Projects 1 and 2 to produce, and iteratively test, a joint host and pathogen gene regulatory network (GRN) model of the progression of MTB infection from containment to active disease. The succes of this systems biology approach to the analysis of MTB disease progression depends on high-quality, high-throughput, global "omics" measurements of biological samples. The Technology Core will supply genomics and proteomics expertise and facilities to the Research Projects as a shared resource. This program proposes expression profiling and proteomics profiling of MTB and host cells during MTB infection to supply the Modeling Core with the global data required for constructing regulatory network models. We will be using expression array transcriptomics and next generation sequencing technologies including RNA-Seq and ChlP-seq. The impact of transcriptional changes on these gene networks will be assayed in both host and pathogen using SWATH-MS and SRM proteomic profiling techniques. Model predictions regarding gene expression will be validated using more targeted high-throughput multiplexed real-time PCR. Gene network circuitry will be validated using ChlP-seq techniques to identify protein/DNA interactions at promoters and proteomic enhanceosome profiling will be used and to define specific ensembles of transcriptional co-factors. The Technology Core will work closely with the Modeling Core and the Data Management and Resources Dissemination Core to utilize, manage, and share these data as efficiently as possible.

Public Health Relevance

Mycobacterium tuberculosis (MTB) causes ~9 million new cases of active disease and 1.4 million deaths each year. By applying a systems biology approach comprising high-throughput, quantitative omics techniques and global, predictive, iterative modeling, and including both host and pathogen gene networks, will provide the scientific community with a novel whole systems view of the disease progression in MTB.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-EC-M)
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Seattle Biomedical Research Institute
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