Grant: Operating Grant - PA: Institute of Genetics (Bridge Funding)

The immune system is complex, rapidly evolving and key to maintaining human health and when dysregulated leads to pathological consequences. The regulation of this system determines whether it can protect us against infections or cause pathology through excessive inflammation. For example the Type I interferon pathway influences responses to viruses, bacterial pathogens and parasites. We propose here to expand this knowledge base by investigating the role in immunity of microRNAs (miRNAs). These miRNAs, processed from primary transcripts, are single-stranded untranslated 21-23 nucleotide RNAs which post-transcriptionally regulate gene expression in multiple genes; although under-studied, there is data linking them to regulation in immunity/inflammation, cancer, cardiology, virology etc. Using Illumina expression profiling, we will assess in parallel miRNA and gene expression responses in the presence or absence of specific microbial stimuli (including infectious agents, LPS, nucleic acids) and host defence peptides. This will provide novel insights into which miRNAs are induced or repressed in responses to pathogens and potential gene targets of these miRNAs. Our recent development of InnateDB, a curated database and analysis platform of the molecular interactions and pathways involved in human and mouse innate immunity will provide an ideal framework to build upon for these analyses. We propose to enrich InnateDB by adding miRNA information, permitting the merging of existing integrated networks of protein-protein and protein-DNA interactions with experimentally determined and/or predicted miRNA-gene networks, adopting or building novel network analysis tools to learn how these are integrated and coordinated/regulated. The novel insights that this will provide will be experimentally validated through knocking out key elements and determining their effects on miRNAs to provide a global picture of the role of miRNA regulation in type I interferon production.