The Bioinformatics Core will employ computational approaches to extract biological insights from the high throughput data sets generated in each of the Projects. The overall aim of the Core will be to help the consortium 1) prioritize genes that are likely to be immune regulators, 2) identify in vivo models where a given point mutation is likely to be most relevant, 3) generate hypotheses regarding the molecular mechanisms underlying immune phenotypes that have been identified, 4) manage and analyze high throughput datasets, in conjunction with the Systems Biology and CyTOF Cores, to determine the mechanism by which the mutation affects immune function, and 5) disseminate all data generated in the Projects and Cores via the Systems Immunology and Mutagenetix web sites (in collaboration with the Annotation Core). Using the substantial in-house database of transcriptomic data from immune cells (both wild-type and various signaling pathway mutants) stimulated with various PAMPs and intact pathogens, the Core has already identified a compendium of candidate regulatory molecules whose function in regulating the immune response is not known. As ENU-induced mutations in these genes are identified, this list of candidates will guide the work in all of the Projects, either by A) allowing enrichment of the pedigree for mutations of interest in order to increase the efficiency of screening (Project 1 and 2), or B) immediately breeding to homozygosity mutations of high interest for more detailed analysis (Project 3). This set of candidates will be continuously refined as the program progresses and more data become available. In addition, the Core will conduct systems-level analysis of the transcriptomic, proteomic, and Cy-TOF data generated in the Systems Biology and CyTOF Cores, to support mechanistic studies of mutations that induce an immune phenotype. The Core will integrate these datasets with networks representing known biological pathways or molecular interactions to predict pathways that are likely to be dysregulated in the mutant immune cells.
The computational analyses undertaken in this Core will suggest hypotheses for how immune cells defend the body against infection. These hypotheses will be tested in the laboratory, extending our understanding of the immune system, and identifying molecules that could be targeted to increase the efficacy of vaccines or to treat infectious and inflammatory diseases.
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