Comprehensive transcriptome profiling of ulcerative colitis mouse model suggests biomarkers and therapeutic targets for human colitis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE155303 | GEO | 2021/03/13
REPOSITORIES: GEO
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Project description:Background: Ulcerative colitis (UC) is a disorder with unknown etiology, and animal models play an essential role in studying its molecular pathophysiology. Here, we aim to identify common conserved pathological UC-related gene expression signatures between humans and mice that can be used as treatment targets and/or biomarker candidates. Methods: To identify differentially regulated protein-coding genes and non-coding RNAs, we sequenced total RNA from the colon and blood of the most widely used dextran sodium sulfate Ulcerative colitis mouse. By combining this with public human Ulcerative colitis data, we investigated conserved gene expression signatures and pathways/biological processes through which these genes may contribute to disease development/progression. Results: Cross-species integration of human and mouse Ulcerative colitis data resulted in the identification of 1442 genes that were significantly differentially regulated in the same direction in the colon and 157 in blood. Of these, 51 genes showed consistent differential regulation in the colon and blood. Less known genes with importance in disease pathogenesis, including SPI1, FPR2, TYROBP, CKAP4, MCEMP1, ADGRG3, SLC11A1, and SELPLG, were identified through network centrality ranking and validated in independent human and mouse cohorts. Conclusion: The identified Ulcerative colitis conserved transcriptional signatures aid in the disease phenotyping and future treatment decisions, drug discovery, and clinical trial design.
| S-EPMC9850088 | biostudies-literature
Project description:BACKGROUND & AIMS: Ulcerative colitis (UC) is an inflammatory bowel disorder with unknown etiology, and given its complex nature, an in vivo model to study its pathophysiology is vital. Animal models play an important role in molecular profiling necessary to pinpoint mechanisms that contribute to human disease. Thus, we aim to identify common conserved gene expression signatures and differentially regulated pathways between human UC and a mouse model hereof, which can be used to identify UC patients from healthy individuals and to suggest novel treatment targets and biomarker candidates. METHODS: Therefore, we performed high-throughput total and small RNA sequencing to comprehensively characterize the transcriptome landscape of the most widely used UC mouse model, the dextran sodium sulfate (DSS) model. We used this data in conjunction with publicly available human UC transcriptome data to compare gene expression profiles and pathways. RESULTS: We identified differentially regulated protein-coding genes, long non-coding RNAs and microRNAs from colon and whole blood of UC mice and further characterized the involved pathways and biological processes through which these genes may contribute to disease development and progression. By integrating human and mouse UC datasets, we suggest a set of 51 differentially regulated genes in UC colon and blood that may improve molecular phenotyping, as well as aid in treatment decisions, drug discovery and the design of clinical trials. CONCLUSION: Global transcriptome analysis of the DSS-UC mouse model supports its use as an efficient high-throughput tool to discover new targets for therapeutic and diagnostic applications in human UC through identifying relationships between gene expression and disease phenotype.
2021-03-13 | GSE155302 | GEO
Project description:BACKGROUND & AIMS: Ulcerative colitis (UC) is an inflammatory bowel disorder with unknown etiology, and given its complex nature, an in vivo model to study its pathophysiology is vital. Animal models play an important role in molecular profiling necessary to pinpoint mechanisms that contribute to human disease. Thus, we aim to identify common conserved gene expression signatures and differentially regulated pathways between human UC and a mouse model hereof, which can be used to identify UC patients from healthy individuals and to suggest novel treatment targets and biomarker candidates. METHODS: Therefore, we performed high-throughput total and small RNA sequencing to comprehensively characterize the transcriptome landscape of the most widely used UC mouse model, the dextran sodium sulfate (DSS) model. We used this data in conjunction with publicly available human UC transcriptome data to compare gene expression profiles and pathways. RESULTS: We identified differentially regulated protein-coding genes, long non-coding RNAs and microRNAs from colon and whole blood of UC mice and further characterized the involved pathways and biological processes through which these genes may contribute to disease development and progression. By integrating human and mouse UC datasets, we suggest a set of 51 differentially regulated genes in UC colon and blood that may improve molecular phenotyping, as well as aid in treatment decisions, drug discovery and the design of clinical trials. CONCLUSION: Global transcriptome analysis of the DSS-UC mouse model supports its use as an efficient high-throughput tool to discover new targets for therapeutic and diagnostic applications in human UC through identifying relationships between gene expression and disease phenotype.
2021-03-13 | GSE155301 | GEO
Project description:Comprehensive transcriptome profiling of ulcerative colitis mouse model suggests biomarkers and therapeutic targets for human colitis
| PRJNA649266 | ENA
Project description:Comprehensive transcriptome profiling of ulcerative colitis mouse model suggests biomarkers and therapeutic targets for human colitis [RNA-Seq]
| PRJNA649271 | ENA
Project description:Comprehensive transcriptome profiling of ulcerative colitis mouse model suggests biomarkers and therapeutic targets for human colitis [miRNA-Seq]
| PRJNA649270 | ENA
Project description:The clinical phenotype of human dilated cardiomyopathy (DCM) encompasses a broad spectrum of etiologically distinct disorders. As targeting of etiology-related pathogenic pathways may be more efficient than current standard heart failure treatment, we obtained the genomic expression profile of a DCM subtype characterized by cardiac inflammation to identify possible new therapeutic targets in humans. In this inflammatory cardiomyopathy (DCMi), a distinctive cardiac expression pattern not described in any previous study of cardiac disorders was observed. Two significantly altered gene networks of particular interest and possible interdependence centered around the cysteine-rich angiogenic inducer 61 (CYR61) and adiponectin (APN) gene. CYR61 overexpression, as in human DCMi hearts in situ, was similarly induced by inflammatory cytokines in vascular endothelial cells in vitro. APN was strongly downregulated in DCMi hearts and completely abolished cytokine-dependent CYR61 induction in vitro. Dysbalance between the CYR61 and APN networks may play a pathogenic role in DCMi and contain novel therapeutic targets. Multiple immune cell-associated genes were also deregulated (e.g., chemokine ligand 14, interleukin-17D, nuclear factors of activated T cells). In contrast to previous investigations in patients with advanced or end-stage DCM where etiology-related pathomechanisms are overwhelmed by unspecific processes, the deregulations detected in this study occurred at a far less severe and most probably fully reversible disease stage.
| S-EPMC1820750 | biostudies-literature
Project description:Background:Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancy worldwide. Accumulating evidences have highlighted the importance of transcriptome data during HNSCC tumorigenesis. The aim of this study was to identify significant genes as effective biomarkers for HNSCC and constructed miRNA-mRNA regulatory network for a more comprehensive understanding of the underlying molecular mechanisms. Methods:A total of four independent microarrays conducted on HNSCC samples were downloaded from the Gene Expression Omnibus (GEO) and analyzed through R software. FunRich was applied to predict potential transcription factors and targeted genes of miRNAs. Protein-protein interaction (PPI) network and miRNA-mRNA regulatory network were constructed in Cytoscape. Additionally, the database for annotation, visualization, and integrated discovery (DAVID) was utilized to perform GO and KEGG pathway enrichment analyses. Validation of gene expression levels was conducted by online databases and qPCR experiments. Results:A total of 35 and 193 differentially expressed miRNAs (DEMs) and mRNAs (DEGs) were screened out by the limma package in R. The interactive network of the overlapping DEGs presented three significant modules and ten hub genes (FN1, MMP3, SPP1, STAT1, LOX, CXCL5, CXCL11, ISG15, IFIT3, and RSAD2). Predicted target genes of DEMs were visualized in Cytoscape and six miRNA-mRNA regulatory pairs were identified. Further validation demonstrated the upregulation of SLC16A1 and COL4A1 in HNSCC. Conclusions:We performed an integrated and comprehensive bioinformatics analysis of miRNAs and mRNAs in HNSCC, contributing to explore the underlying regulatory mechanisms and to identify genetic biomarkers and therapeutic targets for HNSCC.
| S-EPMC7186651 | biostudies-literature
Project description: Not available
| S-DIXA-D-1141 | biostudies-other
Project description:Background and aimsTo define pharmacodynamic and efficacy biomarkers in ulcerative colitis [UC] patients treated with PF-00547659, an anti-human mucosal addressin cell adhesion molecule-1 [MAdCAM-1] monoclonal antibody, in the TURANDOT study.MethodsTranscriptome, proteome and immunohistochemistry data were generated in peripheral blood and intestinal biopsies from 357 subjects in the TURANDOT study.ResultsIn peripheral blood, C-C motif chemokine receptor 9 [CCR9] gene expression demonstrated a dose-dependent increase relative to placebo, but in inflamed intestinal biopsies CCR9 gene expression decreased with increasing PF-00547659 dose. Statistical models incorporating the full RNA transcriptome in inflamed intestinal biopsies showed significant ability to assess response and remission status. Oncostatin M [OSM] gene expression in inflamed intestinal biopsies demonstrated significant associations with, and good accuracy for, efficacy, and this observation was confirmed in independent published studies in which UC patients were treated with infliximab or vedolizumab. Compared with the placebo group, intestinal T-regulatory cells demonstrated a significant increase in the intermediate 22.5-mg dose cohort, but not in the 225-mg cohort.ConclusionsCCR9 and OSM are implicated as novel pharmacodynamic and efficacy biomarkers. These findings occur amid coordinated transcriptional changes that enable the definition of surrogate efficacy biomarkers based on inflamed biopsy or blood transcriptomics data.ClinicalTrials.gov identifierNCT01620255.
| S-EPMC6535501 | biostudies-literature