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GSE141905
Homo sapiens
12 Downloadable Samples
Affymetrix Clariom S Human array (clariomshuman)
Description
Fibrogenic processes instigate fatal chronic diseases leading to organ failure and death. Underlying biological processes involve induced massive deposition of extracellular matrix (ECM) by aberrant fibroblasts. We subjected diseased primary human lung fibroblasts to an advanced 3D phenotypic high-content assay and screened a library of FDA/EMA approved small molecules for inhibiting ECM deposition. Fibrotic Pattern Detection by Artificial Intelligence (FANTAIL) identified Tranilast as an effective inhibitor, however, by structure-activity relationship studies we found N-(2-butoxyphenyl)-3-(phenyl)acrylamides (N23Ps) as a novel and highly potent compound class. N23Ps suppressed myofibroblast transdifferentiation, ECM deposition, cellular contractility, and altered cell shapes, thus advocating a unique mode of action. Mechanistically, transcriptomics identified SMAD (de)ubiquitination/Smurf2 as a potential therapeutic target network. Antifibrotic activity of N23Ps was verified by proteomics in a human ex vivo tissue fibrosis disease model, suppressing profibrotic markers SERPINE1/PAI1 and CXCL8/IL8. Conclusively, these data suggest N23Ps as a novel class of highly potent compounds with implications for inhibiting organ fibrosis in patients.
Publication Title
Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 44 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Type 1 diabetes is a multigenic disease caused by T-cell mediated destruction of the insulin producing -cells. Although conventional (targeted) approaches of identifying causative genes have advanced our knowledge of this disease, many questions remain unanswered. Using a whole molecular systems study, we unraveled the genes/molecular pathways that are altered in CD4 T-cells from young NOD mice prior to insulitis (lymphocytic infiltration into the pancreas). Many of the CD4 T-cell altered genes lie within known diabetes susceptibility regions (Idd), including several genes in the diabetes resistance region Idd13 and two genes (Khdrbs1 and Ptp4a2) in the CD4 T-cell diabetogenic activity region Idd9/11. Alterations involved apoptosis/cell proliferation and metabolic pathways (predominant at 2 weeks), inflammation and cell signaling/activation (predominant at 3 weeks), and innate and adaptive immune responses (predominant at 4 weeks). We identified several factors that may regulate these abnormalities: IRF-1, HNF4A, TP53, BCL2L1 (lies within Idd13), IFNG, IL4, IL15, and prostaglandin E2, which were common to all 3 ages; AR and IL6 to 2 and 4 weeks; and Interferon (IFN-I) and IRF-7 to 3 and 4 weeks. Others were unique to the various ages (e. g. MYC, JUN, and APP to 2 weeks; TNF, TGFB1, NFKB, ERK, and p38MAPK to 3 weeks; and IL12 and STAT4 to 4 weeks). Our data suggest that diabetes resistance genes in Idd13 and Idd9/11, and BCL2L1, IL6-AR and IFNG-IRF-1-IFN-I/IRF-7-IL12 pathways play an important role in CD4 T-cells in the early pathogenesis of autoimmune diabetes. Thus, the alternative approach of investigation at the molecular systems level has captured new information, which combined with validation studies, offers the opportunity to test hypotheses on the role played by the genes/molecular pathways identified in this study, to understand better the mechanisms of autoimmune diabetes in CD4 T-cells, and to develop new therapeutic strategies for the disease.
Publication Title
Molecular pathway alterations in CD4 T-cells of nonobese diabetic (NOD) mice in the preinsulitis phase of autoimmune diabetes.
Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 60 Downloadable Samples
- Affymetrix Mouse Expression 430A Array (moe430a)
Description
Islet leukocytic infiltration (insulitis) is first obvious at around 4 weeks of age in the NOD mouse a model for human type 1 diabetes (T1DM). The molecular events leading to insulitis are poorly understood. Since TIDM is caused by numerous genes, we hypothesized that multiple molecular pathways are altered and interact to initiate this disease.
Publication Title
Molecular phenotyping of immune cells from young NOD mice reveals abnormal metabolic pathways in the early induction phase of autoimmune diabetes.
Sample Metadata Fields
Age, Specimen part
View Samples- Drosophila melanogaster
- 27 Downloadable Samples
- Affymetrix Drosophila Genome 2.0 Array (drosophila2)
Description
Hypoxia plays a key pathogenic role in the outcome of many pathologic conditions. To elucidate how organisms successfully adapt to hypoxia, a population of Drosophila melanogaster was generated, through an iterative selection process, that is able to complete its lifecycle at 4% O2, a level lethal to the starting parental population. Transcriptomic analysis of flies adapted for >200 generations was performed to identify pathways and processes that contribute to the adapted phenotype, comparing gene expression of three developmental stages with generation-matched control flies. A third group was included, hypoxia-adapted flies reverted to 21% O2 for five generations, to address the relative contributions of genetics and hypoxic environment to the gene expression differences. We identified the largest number of expression differences in 0.5-3 hr post-eclosion adult flies that were hypoxia-adapted and maintained in 4% O2, and found evidence that changes in Wnt signaling contribute to hypoxia tolerance in flies.
Publication Title
Wnt pathway activation increases hypoxia tolerance during development.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 15 Downloadable Samples
- Affymetrix Mouse Gene 2.1 ST Array (mogene21st)
Description
Cerebellar development requires regulated proliferation of cerebellar granule neuron progenitors (CGNPs). Inadequate CGNP proliferation causes cerebellar hypoplasia while excessive CGNP proliferation can cause medulloblastoma, the most common malignant pediatric brain tumor. Although Sonic Hedgehog (SHH) signaling is known to activate CGNP proliferation, the mechanisms down-regulating proliferation are less defined. We investigated CGNP regulation by GSK-3, which down-regulates proliferation in the forebrain, gut and breast by suppressing mitogenic WNT signaling. In striking contrast, we found that co-deleting Gsk-3α and Gsk-3β blocked CGNP proliferation, causing severe cerebellar hypoplasia. Transcriptomic analysis showed activated WNT signaling and up-regulated Cdkn1a in Gsk-3-deleted CGNPs. These data show that a GSK-3/WNT axis modulates the developmental proliferation of CGNPs and the pathologic growth of SHH-driven medulloblastoma. The requirement for GSK-3 in SHH-driven proliferation suggests that GSK-3 may be targeted for SHH-driven medulloblastoma therapy.
Publication Title
GSK-3 modulates SHH-driven proliferation in postnatal cerebellar neurogenesis and medulloblastoma.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Expression 430A Array (moe430a)
Description
The molecular etiology of invididual differences in complex behavior traits and susceptibility to psychiatric illness remains incomplete. Using an unbiased genetic approach in a mouse model, Quantitative Trait Loci (QTL) influencing anxiety-like behaviors and beta-carboline-induced seizure vulnerability have been mapped to the distal portion of mouse chromosome 10 and an interval specific congenic strain (ISCS; A.B6chr10; 66 cM to telomere) was developed. This A.B6chr10 strain facilitated defining the behavioral influences of this region as well as gene expression profiling to identify candidate gene(s) underlying this QTL. By microarray studies, an unsuspected E3 Ubiquitin Ligase, Ring Finger 41 (Rnf41 / Neuregulin Receptor Degrading Protein1; Nrdp1) was differentially expressed in the region of interest, comparing the hippocampi of A/J vs A.B6chr10 mice as well as A/J vs B6 mice. By RT-PCR, Rnf41 expression levels were significantly increased 1.5 and 1.3-fold in the hippocampi of C57BL6/J and A.B6chr10 mice compared to A/J mice, respectively. In addition, protein levels of Rnf41 were increased in hippocampi of B6 mice compared to A/J mice across postnatal development with a 5.5-fold difference at P56. Among LxS recombinant inbred mice (N=33), Rnf41 hippocampal mRNA expression levels were significantly correlated with open field behavior (r= .454, p=.0073). Re-analyzing a microarray database of human post-mortem prefrontal cortex (Brodmanns Area 46/10), RNF41 mRNA expression levels were reduced significantly in patients with major depression and bipolar disorder compared to unaffected controls. Overall, Rnf41 is a pleiotropic candidate gene for anxiety-like behaviors, depression, and vulnerability to seizures. RNF41 and its binding partners provide novel etiological pathways for influencing behavior, highlighting a potential role for the ubiquitin proteasome system in psychiatric illness.
Publication Title
An E3 ubiquitin ligase, Really Interesting New Gene (RING) Finger 41, is a candidate gene for anxiety-like behavior and beta-carboline-induced seizures.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 8 Downloadable Samples
IlluminaHiSeq2500
Description
We describe a chemical method to label and purify 4-thiouridine (s4U) -containing RNA. We demonstrate that methanethiolsulfonate (MTS) reagents form disulfide bonds with s4U more efficiently than the commonly used HPDP-biotin, leading to higher yields and less biased enrichment. This increase in efficiency allowed us to use s4U-labeling to study global microRNA (miRNA) turnover in proliferating cultured human cells without perturbing global miRNA levels or the miRNA processing machinery. This improved chemistry will enhance methods that depend on tracking different populations of RNA such as 4-thiouridine-tagging to study tissue-specific transcription and dynamic transcriptome analysis (DTA) to study RNA turnover. Overall design: s4U metabolic labeling of RNA in 293T cells, followed by biochemical enrichment of labeled RNA with two biotinylation reagents, RNAs >200nt and miRNAs in separate experiments
Publication Title
Tracking Distinct RNA Populations Using Efficient and Reversible Covalent Chemistry.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
The normal growth and function of mammary epithelial cells depend on interactions with the supportive stroma. Alterations in this communication can lead to the progression or expansion of malignant growth. The human mammary gland contains two distinctive types of fibroblasts within the stroma. The epithelial cells are surrounded by loosely connected intralobular fibroblasts, which are subsequently surrounded by the more compacted interlobular fibroblasts. The different proximity of these fibroblasts to the epithelial cells suggests distinctive functions for these two subtypes. In this report, we compared the gene expression profiles between the two stromal subtypes.
Publication Title
Interlobular and intralobular mammary stroma: genotype may not reflect phenotype.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 8 Downloadable Samples
- Illumina HiSeq 2500
Description
Identification of novel differentially expressed genes in human M1 and M2 macrophages using RNA-Seq Overall design: RNA-Seq was performed using RNA from M1 and M2-polarized macrophages from 4 biological replicates
Publication Title
Transcriptional profiling identifies novel regulators of macrophage polarization.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Substantial experimental evidence has shown that dedifferentiation from an epithelial state to a mesenchymal-like state (EMT) drives tumor cell metastasis. This transition facilitates tumor cells to acquire motility and invasive features. Intriguingly, tumor cells at the metastatic site are primarily epithelial, and it is believed that they re-differentiate back to an epithelial state by a process called mesenchymal to epithelial transition (MET). However, there is little in vivo evidence to support the MET process.
Publication Title
E-cadherin re-expression shows in vivo evidence for mesenchymal to epithelial transition in clonal metastatic breast tumor cells.
Sample Metadata Fields
Specimen part, Cell line
View Samples