Mus musculus
Ontology highlight
ABSTRACT:
OTHER RELATED OMICS DATASETS IN: E-GEOD-15318
PROVIDER: PRJNA115851 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Background and Aims: In the interleukin-10-deficient (Il10-/-) mouse model of IBD, 10 quantitative trait loci (QTL) have been shown to be associated with colitis susceptibility by linkage analyses on experimental crosses of highly susceptible C3H/HeJBir (C3Bir)-Il10-/- and partially resistant C57BL/6J (B6)-Il10-/- mice. The strongest locus (C3Bir-derived cytokine deficiency-induced colitis susceptibility [Cdcs]1 on Chromosome [Chr] 3) controlled multiple colitogenic subphenotypes and contributed the vast majority to the phenotypic variance in cecum and colon. This was demonstrated by interval-specific Chr 3 congenic mice wherein defined regions of Cdcs1 from C3Bir or B6 were bred into the IL-10-deficient reciprocal background and altered the susceptible or resistant phenotype. Furthermore, this locus likely acts by inducing innate hypo- and adaptive hyperresponsiveness, associated with impaired NFΚB responses of macrophages. The aim of the present study was to dissect the complexity of Cdcs1 by further development and characterization of reciprocal Cdcs1 congenic strains and to identify potential candidate genes in the congenic interval. Material and Methods: In total, 15 reciprocal congenic strains were generated from Il10-/- mice of either C3H/HeJBir or C57BL/6J backgrounds by 10 cycles of backcrossing. Colitis activity was monitored by histological grading. Candidate genes were identified by fine mapping of congenic intervals, sequencing, microarray analysis and a high-throughput real-time RT-PCR approach using bone marrow-derived macrophages. Results: Within the originally identified Cdcs1-interval, three independent regions were detected that likely contain susceptibility-determining genetic factors (Cdcs1.1, Cdcs1.2, and Cdcs1.3). Combining results of candidate gene approaches revealed Fcgr1, Cnn3, Larp7, and Alpk1 as highly attractive candidate genes with polymorphisms in coding or regulatory regions and expression differences between susceptible and resistant mouse strains. Conclusions: Subcongenic analysis of the major susceptibility locus Cdcs1 on mouse chromosome 3 revealed a complex genetic structure. Candidate gene approaches revealed attractive genes within the identified regions with homologs that are located in human susceptibility regions for IBD. Experiment Overall Design: Bone marrow derived macrophages (BMDM) of colitis susceptible C3Bir-Il10-/- and colitis resistant B6-Il10-/- as well as the Il10-/- reciprocal congenic strains CB-R1 (C3Bir genetic background carrying a long congenic chromosome 3 element containing Cdcs1 from B6, rendering this formerly susceptible background resistant) and BC-R3 (B6 genetic background that carries the Cdcs1-region of C3Bir) were cultured and stimulated with flagellin or left unstimulated. BMDM were obtained from 3 male mice per genotype and cultured in polystyrene 6-well culture plates. Before RNA-isolation, 3 wells per plate were stimulated with Cbir1 flagellin (and subsequently pooled for RNA isolation), the other 3 wells left unstimulated (and also pooled). In total, these experiments were replicated three times in order to perform microarray analyses in triplicates.
2009-10-09 | E-GEOD-15318 | biostudies-arrayexpress
Project description:Background and Aims: In the interleukin-10-deficient (Il10-/-) mouse model of IBD, 10 quantitative trait loci (QTL) have been shown to be associated with colitis susceptibility by linkage analyses on experimental crosses of highly susceptible C3H/HeJBir (C3Bir)-Il10-/- and partially resistant C57BL/6J (B6)-Il10-/- mice. The strongest locus (C3Bir-derived cytokine deficiency-induced colitis susceptibility [Cdcs]1 on Chromosome [Chr] 3) controlled multiple colitogenic subphenotypes and contributed the vast majority to the phenotypic variance in cecum and colon. This was demonstrated by interval-specific Chr 3 congenic mice wherein defined regions of Cdcs1 from C3Bir or B6 were bred into the IL-10-deficient reciprocal background and altered the susceptible or resistant phenotype. Furthermore, this locus likely acts by inducing innate hypo- and adaptive hyperresponsiveness, associated with impaired NFΚB responses of macrophages. The aim of the present study was to dissect the complexity of Cdcs1 by further development and characterization of reciprocal Cdcs1 congenic strains and to identify potential candidate genes in the congenic interval. Material and Methods: In total, 15 reciprocal congenic strains were generated from Il10-/- mice of either C3H/HeJBir or C57BL/6J backgrounds by 10 cycles of backcrossing. Colitis activity was monitored by histological grading. Candidate genes were identified by fine mapping of congenic intervals, sequencing, microarray analysis and a high-throughput real-time RT-PCR approach using bone marrow-derived macrophages. Results: Within the originally identified Cdcs1-interval, three independent regions were detected that likely contain susceptibility-determining genetic factors (Cdcs1.1, Cdcs1.2, and Cdcs1.3). Combining results of candidate gene approaches revealed Fcgr1, Cnn3, Larp7, and Alpk1 as highly attractive candidate genes with polymorphisms in coding or regulatory regions and expression differences between susceptible and resistant mouse strains. Conclusions: Subcongenic analysis of the major susceptibility locus Cdcs1 on mouse chromosome 3 revealed a complex genetic structure. Candidate gene approaches revealed attractive genes within the identified regions with homologs that are located in human susceptibility regions for IBD.
2009-10-01 | GSE15318 | GEO
Project description:The gut microbiome consists of a multi-kingdom microbial community. Whilst the role of bacteria as causal contributors governing host physiological development is well established, the role of fungi remains to be determined. Here, we use germ-free mice colonized with defined species of bacteria, fungi, or both to differentiate the causal role of fungi on microbiome assembly, immune development, susceptibility to colitis, and airway inflammation. Fungal colonization promotes major shifts in bacterial microbiome ecology, and has an independent effect on innate and adaptive immune development in young mice. While exclusive fungal colonization is insufficient to elicit overt dextran sulfate sodium-induced colitis, bacterial and fungal co-colonization increase colonic inflammation. Ovalbumin-induced airway inflammation reveals that bacterial, but not fungal colonization is necessary to decrease airway inflammation, yet fungi selectively promotes macrophage infiltration in the airway. Together, our findings demonstrate a causal role for fungi in microbial ecology and host immune functionality, and therefore prompt the inclusion of fungi in therapeutic approaches aimed at modulating early life microbiomes.
2022-01-14 | MTBLS1679 | MetaboLights
Project description:Chronic inflammation of the intestine has been associated with an elevated risk of developing colorectal cancer. Recent association studies have highlighted the role of genetic predisposition in the etiology of colitis and started to unravel its complexity. However, the genetic factors influencing the progression from colon inflammation to tumorigenesis are not known. We used Helicobacter hepaticus-induced colitis in a 129.RAG(-/-) mouse model to explore early onset of the disease. Experiments purpose and justifications: to elucidate early genes and pathways changed in the mouse strain susceptible to innate colitis triggered by Hh infection. Experimental factors: steady state, and days 2 and 4 of infection (n=4 mice per condition). The time course is validated on the same samples using qPCR for inflammatory genes. Samples: RNA from proximal mouse colon. Two mouse genetic strains are compared 129Rag-/- (susceptible) and 129.R17Rag-/- (protected from colitis).
2018-07-30 | E-MTAB-7075 | biostudies-arrayexpress
Project description:Chronic inflammatory bowel disease (IBD) causes disability, suffering and risk of colon cancer in over 30 million people globally. Here, we investigate 3 kindreds of IBD with mutations in the N-acetylgalactosamide alpha-2,6-sialyltransferase 1/ST6GALNAC1 (ST6) glycosyltransferase gene that is uniquely expressed in the goblet cells (GCs). These mutations cause defective sialic acid (SA) conjugation, elimination of the onco-antigen S-Tn (Sialyl-Tn), and altered glycosylation of the MUC2 protein, a key component of intestinal mucus. Decreased MUC2 sialylation increases susceptibility to bacterial proteolytic degradation and compromises the gastrointestinal (GI) mucus barrier. Mice harboring the patient ST6 mutations recapitulate human colitis and reveal that defective sialylation causes dysbiosis, butyrate overproduction, and impaired GI stem cell proliferation during injury. Thus, this new genetic disease illustrates how sialylation controls host-microbe homeostasis and reveals several new potential approaches to IBD treatment.
2022-03-17 | PXD028239 | Pride
Project description:Sle1c is a sublocus of the NZM2410-derived Sle1 major susceptibility locus. We have previously shown that Sle1c contributes to lupus pathogenesis by conferring CD4+ T cell-intrinsic hyperactivation and increased susceptibility to chronic graft-versus-host disease (cGVHD) that mapped to the centromeric portion of the locus. In this study, we have refined the centromeric sublocus to a 675Kb interval, termed Sle1c2. Recombinant congenic strains expressing Sle1c2 exhibited a T cell-intrinsic CD4+ T cell hyperactivation and cGVHD susceptibility, similar to mice with the parental Sle1c. We performed a microarray analysis on CD4+ T cells to gain insights into the transcriptional programs that regulate the hyperactivation conferred by Sle1c2. CD4+ T cell cDNA was prepared from spenocytes from 5 mice from each strain and B6.Sle1c2 gene expression was compared to B6 gene expresion.
2011-08-29 | E-GEOD-31702 | biostudies-arrayexpress
Project description:Primary cilia (PC) are important signaling hubs in cells and we explored their role in colorectal cancer (CRC) and colitis. In the colon we found PC to be mostly present on different subtypes of fibroblasts and exposure of mice to either chemically induced colitis-associated colon carcinogenesis (CAC) or dextran sodium sulfate (DSS)-induced acute colitis decreased PC numbers. We employed conditional knock-out strains for the PC essential genes, Kif3A and Ift88, to generate mice with reduced numbers of PC on colonic fibroblasts. These mice showed an increased susceptibility in the CAC model as well as in DSS-induced colitis. Secretome and immunohistochemical analyses of DSS-treated mice displayed an elevated production of the pro-inflammatory cytokine IL-6 in PC-deficient colons. An inflammatory environment diminished PC presence in primary fibroblast cultures. This was triggered by IL-6 as identified by RNAseq analysis together with blocking experiments, suggesting an activation loop between IL-6 production and PC loss. Notably, an analysis of PC presence on biopsies of patients with ulcerative colitis as well as CRC patients revealed decreased numbers of PC on colonic fibroblasts in pathological versus surrounding normal tissue. Taken together, we provide evidence that a decrease in colonic PC numbers promotes colitis and CRC.
2022-11-29 | PXD033440 | Pride
Project description:Sle1c is a sublocus of the NZM2410-derived Sle1 major susceptibility locus. We have previously shown that Sle1c contributes to lupus pathogenesis by conferring CD4+ T cell-intrinsic hyperactivation and increased susceptibility to chronic graft-versus-host disease (cGVHD) that mapped to the centromeric portion of the locus. In this study, we have refined the centromeric sublocus to a 675Kb interval, termed Sle1c2. Recombinant congenic strains expressing Sle1c2 exhibited a T cell-intrinsic CD4+ T cell hyperactivation and cGVHD susceptibility, similar to mice with the parental Sle1c. We performed a microarray analysis on CD4+ T cells to gain insights into the transcriptional programs that regulate the hyperactivation conferred by Sle1c2.
2011-08-30 | GSE31702 | GEO
Project description:For most multigenic disorders, clinical manifestation (penetrance) and presentation (expressivity) are likely to be an outcome of genetic interaction between multiple susceptibility genes. Here, using gene knockouts in mice we evaluated genetic interaction between loss of Ret and loss of Sema3d, two Hirschsprung disease (HSCR) susceptibility genes. We intercrossed Ret and Sema3d double null heterozygotes to generate mice with the nine possible genotypes and assessed survival by counting various genotypes, myenteric plexus development by acetylcholinesterase (AchE) staining and embryonic day 12.5 (E12.5) gut transcriptome by RNA-sequencing. Survival rates of Ret wildtype, null heterozygote and null homozygote mice at E12.5, birth and weaning were not influenced by the genotypes at Sema3d locus and vice-versa. Loss of myenteric plexus was observed only in all Ret null homozygotes, irrespective of the genotypes at Sema3d locus, and Sema3d null heterozygote and homozygote mice had normal gut innervation. As compared to wildtype mice gut gene expression, loss of Ret in null homozygotes led to differential expression of ~300 genes, whereas loss of Sema3d in null homozygotes had no major consequence and there was no evidence supporting major interaction between the two genes influencing gut transcriptome. Overall, given the null alleles and phenotypic assays used, we did not find evidence for genetic interaction between Ret and Sema3d affecting survival, myenteric plexus formation or gut transcriptome.
2017-03-28 | GSE89627 | GEO
Project description:Inflammation has pleiotropic effects on carcinogenesis and tumor progression. Signaling through the adaptor protein MyD88 promotes carcinogenesis in several chemically induced cancer models. Interestingly, we observed a protective role for MyD88 in the development of AOM/DSS colitis-associated cancer. The inability of Myd88-/- mice to heal ulcers generated upon injury creates an inflammatory environment that increases the frequency of mutations and results in a dramatic increase in adenoma formation and cancer progression. Susceptibility to colitis development and enhanced polyp formation were also observed in Il18-/- mice upon AOM/DSS treatment, suggesting that the phenotype of MyD88 knockouts is in part due to their inability to signal through the IL-18 receptor. This study revealed a previously unknown level of complexity surrounding MyD88 activities downstream of different receptors that differentially impact tissue homeostasis and carcinogenesis. The Myd88 knockout mice were backcrossed to obtain at least 98% congenicity to B6NCr background. As control groups, wild type mice of identical background were used. Ten biological repeats were performed for the treated wild type and Myd88 samples. Six biological repeats were performed for the untreated wild type and Myd88 samples.
2010-07-30 | E-GEOD-19793 | biostudies-arrayexpress