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ICH Induces Monocyte-Related Gene Expression Within Six Hours; A Study of Global Transcriptional Profiling in Swine ICH

ABSTRACT: Intracerebral hemorrhage (ICH) is a severe neurological disorder with no proven treatment. Our prior research identified a significant association with monocyte level and ICH mortality. To further advance our understanding, we sought to identify the gene expression changes after ICH using a swine model to test the hypothesis that ICH would result in changes in peripheral blood mononuclear cell (PBMC) gene expression. There were 182 significantly upregulated and 153 significantly down-regulated DEGs after ICH. Consistent with findings in humans, significant GO and KEGG pathways were those primarily related to inflammation, immune response, and response to infectious pathogens. There were five genes, all with increased expression post-ICH, that were repeatedly identified as significant DEGs in the statistically significant KEGG pathways: CD14 (cluster of differentiation 14), TLR4 (toll-like receptor-4), CXCL8 (CXC motif chemokine-8), IL-18 (interleukin-18), and CXCL2 (CXC motif chemokine-2). Conclusion: ICH induced changes in PBMC gene expression within 6 hours of onset. DEGs that were highly expressed in the significant biological pathways included those related to inflammation, the immune response, and, more specifically, monocyte activation. Further research is needed to determine if these changes affect outcomes and may represent new therapeutic targets.

ORGANISM(S): Sus scrofa

PROVIDER: GSE124624 | GEO | 2019/03/01

REPOSITORIES: GEO

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Project description:Introduction: Intracerebral hemorrhage (ICH) is a severe neurological disorder with no proven treatment. microRNA (miRNA) are short, noncoding nucleic acids that are critical regulators gene expression and promising novel therapeutic targets. Our prior research of mRNA-seq in swine demonstrated that ICH increased inflammatory gene expression within six hours of onset. We now present findings from an integrated analysis of miRNA-seq and mRNA-seq in peripheral blood mononuclear cells (PBMCs) from swine ICH. We tested the hypothesis that ICH would induce miRNA within six hours and that differentially expressed (DE) inflammatory genes would be targets of the DE miRNA. Methods: In 10 pigs, one PBMC sample was collected immediately prior to ICH induction and a second six hours later; miRNA-seq and mRNA-seq were performed. To determine the miRNA that primarily regulated the DE mRNA, an aggregate score was calculated for each miRNA of interest that incorporated the combined summary statistics of its DE target mRNA. Networks of molecular interactions were generated for the target mRNA and the combined miRNA/target mRNA. Results: A total of 227 miRNA were identified with alignment to the Sus scrofa (swine) genome, and 46 were DE (FDR <0.05). When analyzed with the aggregate scoring calculation, the miRNA that were most essential for regulating the DE mRNA included the following, all of which were downregulated post-ICH: miR-29a, miR-29b, miR-31, miR-34c, miR-125a, miR-132, miR-142, miR-150, miR-151a, miR-181a, and miR-186. A highly connected network of interactions was generated from these miRNA and their target mRNA. Conclusion: ICH strongly induced numerous miRNA/mRNA targets in swine PBMCs within six hours of onset. To our knowledge, this is the first integrated analysis of miRNA-seq and mRNA-seq in any study of ICH and the first report of miRNA in swine ICH. Further research is needed to determine whether these miRNA are potential therapeutic targets, including analyzing interventions such as miRNA overexpression or inhibition

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ICH Induces Monocyte-Related Gene Expression Within Six Hours; A Study of Global Transcriptional Profiling in Swine ICH

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