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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of mouse model of Epidermolysis bullosa simplex keratin5 knockout epidermis response to doxycycline treatment

ABSTRACT: Epidermolysis bullosa simplex (EBS) is a skin disorder caused by mutations in keratin (K) 5 or K14 genes. Little effect therapy is available.Following clinical reports, we applied the small molecule doxycycline to K5-/- mice. We demonstrate that doxycycline extended the survival of neonatal K5-/- mice from less than 1 to up to 8 hours. Microarray and TaqMan real-time PCR showed a downregulation of MMP-13 and IL-1ï¢, indicating an effect of doxycycline on transcription. Our data offer a novel small molecule based therapy approach for EBS. Experiment Overall Design: doxycycline (50 Âµg/mlwith 5 % sucrose) was administered by oral route to pregnant K5+/- females (mated to K5+/- males) starting from E13.5. 5 % sucrose solution was administered to the control group.

ORGANISM(S): Mus musculus

SUBMITTER: Hong Lu

PROVIDER: E-GEOD-7662 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcription profiling of mouse model of Epidermolysis bullosa simplex (EBS) K5-/- skin reveals induction of inflammatory cytokines by a keratin mutation

Project description:Epidermolysis bullosa simplex (EBS) is a skin disorder caused by mutations in keratin (K) 5 or K14 genes. It is widely regarded as a mechanobullous disease, resulting from a weakened cytoskeleton, causing extensive cytolysis. It was postulated by others that certain K14 mutations induce TNF-alfa and increase apoptosis. Here, we report that in K5-/- mice , the mRNA and protein levels of TNF-alfa remain unaltered. Transcriptome analysis of K5-/- mice revealed however, that the pro-inflammatory cytokines interleukin-6 and interleukin-1beta were significantly upregulated at the mRNA level in K5-/- mouse skin. These results were confirmed by TaqMan real-time PCR and ELISA assays. We hypothesize that keratin mutations contribute to EBS in a mouse model by inducing local inflammation that mediates a stress response. Experiment Overall Design: Two groups were K5-/- skin and wildtype . Six animals were included in each group. All the total RNA samples were isolated from tissues taken immediately after birth, and were pooled for later microarray experiments. Using realtime PCR and ELISA analysis confirmed our microarray result.

2008-06-15 | E-GEOD-7663 | biostudies-arrayexpress

Gene expression profile after doxycycline treatment in keratin5 knockout epidermis

Project description:Epidermolysis bullosa simplex (EBS) is a skin disorder caused by mutations in keratin (K) 5 or K14 genes. Little effect therapy is available.Following clinical reports, we applied the small molecule doxycycline to K5-/- mice. We demonstrate that doxycycline extended the survival of neonatal K5-/- mice from less than 1 to up to 8 hours. Microarray and TaqMan real-time PCR showed a downregulation of MMP-13 and IL-1beta, indicating an effect of doxycycline on transcription. Our data offer a novel small molecule based therapy approach for EBS. Keywords: drug treatment, global gene expression comparative profile

2007-05-01 | GSE7662 | GEO

Transcriptional analysis of apoptotic cerebellar granule neurons following rescue by Gip, Sp, Pacap and Igf1

Project description:Primary cultures of Cerebellar Granule Neurons (CGNs) have been extensively utilized to examine the signal transduction mechanisms underlying neuronal apoptosis. We conducted whole-genome expression profiling to decipher the transcriptional program controlling the apoptotic/survival switch in cerebellar granule neurons (CGNs) following the induction of apoptosis by serum and potassium deprivation and their rescue by gastric inhibitory polypeptide (Gip), substance p (Sp), insulin-like growth factor-1 (Igf1) or pituitary adenylyl cyclase-activating polypeptide (Pacap). Our results reveal the transcriptional changes intersecting neuronal apoptosis and survival and form the basis for further functional analyses and pharmacological exploitation to identify neuroprotective drugs. After six days âin vitroâ (DIV), extracellular KCl of CGNs was shifted from 25 to 5 mM for neuronal apoptotic death induction. After two washes with serum-free BME containing 5 mM KCl, neurons were incubated with the same medium for 6 h (K5), while control neurons were incubated with serum free medium supplemented with 25 mM KCl (K25). K5 neurons were also treated with a maximal effective dose of Gip, Sp, Igf1 and Pacap. Four biological replicates (derived from the same litter) for each of the experimental conditions (K25, K5, K5 + Gip; K25, K5, K5 + Sp; K25, K5, K5 + Igf1; K25, K5, K5 + Pacap) were analyzed.

2016-07-03 | E-GEOD-67788 | biostudies-arrayexpress

Murine forestomach epithelial sheets: Controls vs. Sox2 overexpression mutants

Project description:Transcriptional profiling of adult forestomach epithelium comparing K5-CreER controsl with K5-CreER;Rosa26Sox2/Sox2 mutants. Two doses of tamoxifen were given and four weeks later the epithelal sheets were harvested for RNA extraction. Goal was to determine the effects of Sox2 overexpression on epithelial phenotypic changes. Two-condition experiment, wildtype Vs Sox2 overexpression mutant. Biological replicates: 3 control replicates, 3 mutant replicates.

2012-05-08 | E-GEOD-37857 | biostudies-arrayexpress

A compound-based therapy approach for epidermolysis bullosa simplex (EBS)

Project description:Keratin cytoskeletal proteins are crucial for the maintenance of skin integrity. Mutations in genes coding for K5 and K14 cause the human skin disorder epidermolysis bullosa simplex (EBS) leading to substantial alterations in keratin assembly and collapse of keratin filaments into cytoplasmic protein aggregates. The phenotypic consequences of K5 and K14 mutations comprise fragility of basal keratinocytes and skin blistering upon mild mechanical trauma. Treatment of EBS is only supportive and consists primarily of wound care and avoidance of mechanical stress. Besides symptomatic care, no efficient therapeutic treatment is available for EBS. In the present study, we used patient-derived keratinocytes carrying the most frequent K14.R125C mutation as a reproducible EBS model to understand EBS pathomechanisms and to develop a therapy approach aimed to restore a functional keratin network. Numerous post-translational modifications (PTMs) such as phosphorylation have been reported to occur on keratins, which affect the organization of keratin networks. Whether keratin mutations affect the occurrence of PTMs and thereby keratin aggregation in EBS is yet unknown. We find that the K14.R125C mutation alters keratin and keratin-associated protein PTMs in distinct ways and suggest that disease mutations and altered PTMs aggravate keratin aggregation. We reason that chemical compounds affecting the interplay of mutations and PTMs enable the reformation of a keratin cytoskeleton from aggregates are potential candidates for combating EBS.

2022-06-29 | PXD030939 | Pride

Analysis of mRNA expression differences in the skin of Casp-8F/–K5-Cre and Casp-8F/+K5-Cre mice

Project description:This SuperSeries is composed of the following subset Series: GSE17344: Analysis of spatial mRNA expression differences in the skin of Casp-8F/–K5-Cre or Casp-8F/+K5-Cre mice GSE17345: Analysis of temporal mRNA expression changes in cultured keratinocytes from Casp-8F/–K5-Cre and Casp-8F/+K5-Cre mice Refer to individual Series

2009-07-29 | E-GEOD-17365 | biostudies-arrayexpress

Dowling-Meara experiment 2

Project description:Dowling-Meara type epidermolysis bullosa simplex (EBS-DM) is a severe blistering disease, caused by dominant mutations in either the keratin-5 (K5) or keratin-14 (K14) gene. K5 and K14 are the major components of the intermediate filament (IF) network in basal keratinocytes. Due to the dominant nature of EBS-DM, misfolded K5 or K14 proteins are incorporated into intermediate filaments, rendering them sensitive to mechanical stress. Upon trauma, these filaments disrupt and the keratinocytes lyse, leading to intra-epidermal blistering.The dominant nature of K5 and K14 mutations in EBS-DM represents a challenge to gene-therapeutic approaches. Therefore, we investigated the gene expression profile of a K14 mutant keratinocyte cell line (EBDM1) and compared it to the gene expression profile of a wild-type keratinocyte cell line (NEB1). The aim of this study was to identify differentially regulated genes as potential therapeutic targets for the development of new therapies.

2013-07-23 | E-MTAB-1641 | biostudies-arrayexpress

Dowling-Meara experiment 1

Project description:Dowling-Meara type epidermolysis bullosa simplex (EBS-DM) is a severe blistering disease, caused by dominant mutations in either the keratin-5 (K5) or keratin-14 (K14) gene. K5 and K14 are the major components of the intermediate filament (IF) network in basal keratinocytes. Due to the dominant nature of EBS-DM, misfolded K5 or K14 proteins are incorporated into intermediate filaments, rendering them sensitive to mechanical stress. Upon trauma, these filaments disrupt and the keratinocytes lyse, leading to intra-epidermal blistering. The dominant nature of K5 and K14 mutations in EBS-DM represents a challenge to gene therapeutic approaches. Therefore, we investigated the gene expression profile of a K14 mutant keratinocyte cell line (KEB7) and compared it to the gene expression profile of a wild-type keratinocyte cell line (NEB1). The aim of this study was to identify differentially regulated genes as potential therapeutic targets for the development of new therapies.

2013-07-23 | E-MTAB-1640 | biostudies-arrayexpress

Induction of inflammatory cytokines by a keratin mutation in a mouse model for EBS

2007-05-01 | GSE7663 | GEO

Akt signalling leads to stem cell activation and promotes tumour development in epidermis.

Project description:A permantly active form of the oncogene Akt was expressed in the keratinocytes of the basal proliferative layer of the epidermis. Stem cells of the hair follicle expressing the cell surface marker CD34 were isolated. RNA form the CD34(+) and CD34(-) keratinocytes was extracted and and hybridized to Mouse Genome 430 2.0 Affymetrix arrays. Gene expression was compared between CD34(+) hair follicle stem cells and CD34(-) cells isolates from the back skin of K5-myrAkt transgenic mice.

2014-01-26 | E-GEOD-48522 | biostudies-arrayexpress

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