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MicroRNA Profiles in Intestinal Epithelial Cells in a Mouse Model of Sepsis

研究内容の概要Overview

Sepsis is a systemic inflammatory disorder that leads to the dysfunction of multiple organs. In the intestine, the deregulation of the epithelial barrier contributes to the development of sepsis by triggering continuous exposure to harmful factors. However, sepsis-induced epigenetic changes in gene-regulation networks within intestinal epithelial cells (IECs) remain unexplored. In this study, we analyzed the expression profile of microRNAs (miRNAs) in IECs isolated from a mouse model of sepsis generated via cecal slurry injection. Among 239 miRNAs, 14 miRNAs were upregulated, and 9 miRNAs were downregulated in the IEC by sepsis. Upregulated miRNAs in IECs from septic mice, particularly miR-149-5p, miR-466q, miR-495, and miR-511-3p, were seen to exhibit complex and global effects on gene regulation networks. Interestingly, miR-511-3p has emerged as a diagnostic marker in this sepsis model due to its increase in blood in addition to IECs. As expected, mRNAs in the IEC were remarkably altered by sepsis; specifically, 2248 mRNAs were decreased, while 612 mRNAs were increased. This quantitative bias may be possibly derived, at least partly, from the direct effects of the sepsis-increased miRNAs on the comprehensive expression of mRNAs. Thus, current in silico data indicate that there are dynamic regulatory responses of miRNAs to sepsis in IECs. In addition, the miRNAs that were increased with sepsis had enriched downstream pathways, including Wnt signaling, which is associated with wound healing, and FGF/FGFR signaling, which has been linked to chronic inflammation and fibrosis. These modifications in miRNA networks in IECs may lead to both pro- and anti-inflammatory effects in sepsis. The four miRNAs discovered above were shown to putatively target LOX, PTCH1, COL22A1, FOXO1, or HMGA2 via in silico analysis, which were associated with Wnt or inflammatory pathways and selected for further study. The expressions of these target genes were downregulated in sepsis IECs, possibly through posttranscriptional modifications of these miRNAs. Taken together, our study suggests that IECs display a distinctive miRNA profile capable of comprehensively and functionally reshaping the IEC-specific mRNA landscape in a sepsis model.

研究成果をどのように社会に役立てるか
（還元の構想）Giving back to society

1. Development of new treatments: Understanding the miRNAs identified in research and the pathways they influence (e.g., Wnt signaling, FGF/FGFR signaling) can contribute to the development of future treatments. In particular, it is possible to develop treatments and drugs that target these miRNAs.
2. Development of early diagnostic methods: miR-511-3p discovered in research has been shown to increase in the blood, and new diagnostic methods may be developed. Early diagnosis is an essential factor in improving the success rate of treatment.
3. Understanding inflammatory diseases: Studies have shown that changes in miRNAs impact Wnt signaling and inflammatory pathways. This finding could be applied to other inflammatory diseases and lead to the development of new treatment strategies and prevention methods.
4. Advances in personalized medicine: Elucidation of the genes and pathways targeted by specific miRNAs will lead to future treatments and prevention methods based on patients' individual genetic profiles.
5. Expansion of scientific knowledge: Research provides new insights into known information, which contributes to advances in basic science. It is expected that this knowledge will be utilized in future research and education.
Based on these ideas for giving back, it is expected that research results will lead to clinical applications and medical advances, contributing to the health and welfare of society.

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