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 & 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 [miRNA-Seq]
| PRJNA649270 | 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: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
Project description:BackgroundUnbiased studies using different genome-wide methods have identified a great number of candidate biomarkers for diagnosis and treatment response in pediatric ulcerative colitis (UC). However, clinical translation has been proven difficult. Here, we hypothesized that one reason could be differences between inflammatory responses in an inflamed gut and in peripheral blood cells.MethodsWe performed meta-analysis of gene expression microarray data from intestinal biopsies and whole blood cells (WBC) from pediatric patients with UC and healthy controls in order to identify overlapping pathways, predicted upstream regulators, and potential biomarkers.ResultsAnalyses of profiling datasets from colonic biopsies showed good agreement between different studies regarding pathways and predicted upstream regulators. The most activated predicted upstream regulators included TNF, which is known to have a key pathogenic and therapeutic role in pediatric UC. Despite this, the expression levels of TNF were increased in neither colonic biopsies nor WBC. A potential explanation was increased expression of TNFR2, one of the membrane-bound receptors of TNF in the inflamed colon. Further analyses showed a similar pattern of complex relations between the expression levels of the regulators and their receptors. We also found limited overlap between pathways and predicted upstream regulators in colonic biopsies and WBC. An extended search including all differentially expressed genes that overlapped between colonic biopsies and WBC only resulted in identification of three potential biomarkers involved in the regulation of intestinal inflammation. However, two had been previously proposed in adult inflammatory bowel diseases (IBD), namely, MMP9 and PROK2.ConclusionsOur findings indicate that biomarker identification in pediatric UC is complicated by the involvement of multiple pathways, each of which includes many different types of genes in the blood or inflamed intestine. Therefore, further studies for identification of combinatorial biomarkers are warranted. Our study may provide candidate biomarkers for such studies.
| S-EPMC7204128 | biostudies-literature
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