Transcriptomic Repositioning Analysis Identifies mTOR Inhibitor as Potential Therapy for Epidermolysis Bullosa Simplex
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PROVIDER: PRJNA744082 | ENA |
REPOSITORIES: ENA
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Project description:In this study, we characterize significant molecular pathways activated in the blisters that form in EBS and employ a systematic drug repositioning screen to identify promising repositionable drugs for EBS. We implicate the PI3K/AKT/mTOR pathway as central in the EBS disease pathway and further validate our computational repositioning analysis by presenting clinical outcomes of two EBS patients treated with mTOR inhibitors.
2021-07-09 | GSE179508 | GEO
Project description:The goal of this study is to characterize the expression profile of Epidermolysis bullosa simplex-mottled pigmentation (EBS-MP) patient compared with normal subjects using genomic expression analyses. Microarray analyses were performed with RNA isolated from skin biopsies. Robust multiarray analysis (RMA) normalization and Smyth’s moderated t test were used to select differentially expressed genes. Expression profiling comparisons show that 52 genes are differentially expressed in EBS-MP patients compared to control subjects. Difference of expression for three genes (TYR, CCL22 , and ACVR1C ) was validated using real-time reverse transcription–polymerase chain reaction. Twelve genes were related to lipid biosynthesis process, two to keratinisation and skin pigmentation, Nineteen to cell growth and apoptosis, five to immune response and fourteen to predicted or less known function cluster. To our knowledge, the distinctive pattern of gene expression that characterizes EBS-MP versus healthy skin tissue has never been reported. RNA used for the microarrays analysis was isolated from superficial 2mm punch biopsies composed of mainly epidermis with minimal dermis amounts of normal-appearing skin of one EBS-MP patient and seven healthy volunteers.
2012-03-10 | E-GEOD-36406 | biostudies-arrayexpress
Project description:The goal of this study is to characterize the expression profile of Epidermolysis bullosa simplex-mottled pigmentation (EBS-MP) patient compared with normal subjects using genomic expression analyses. Microarray analyses were performed with RNA isolated from skin biopsies. Robust multiarray analysis (RMA) normalization and Smyth’s moderated t test were used to select differentially expressed genes. Expression profiling comparisons show that 52 genes are differentially expressed in EBS-MP patients compared to control subjects. Difference of expression for three genes (TYR, CCL22 , and ACVR1C ) was validated using real-time reverse transcription–polymerase chain reaction. Twelve genes were related to lipid biosynthesis process, two to keratinisation and skin pigmentation, Nineteen to cell growth and apoptosis, five to immune response and fourteen to predicted or less known function cluster. To our knowledge, the distinctive pattern of gene expression that characterizes EBS-MP versus healthy skin tissue has never been reported.
2012-03-10 | GSE36406 | GEO
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-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 µg/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.
2008-06-15 | E-GEOD-7662 | biostudies-arrayexpress
Project description:Epidermolysis Bullosa Simplex (EBS) is the most common form of Epidermolysis Bullosa (EB) and it is mainly inherited in an autosomal dominant manner (prevalence 1/30000 – 1/50000). Several clinical variants have been described based on the mutated gene, the site of blister formation and the anatomical distribution, but the vast majority of the patients display dominant mutations in genes encoding keratin 5 (KRT5) and keratin 14 (KRT14). The lack of functional keratin intermediate filaments causes basal keratinocytes to exhibit a dramatic cytoplasmatic softening and rupture, when subjected to minor mechanical traction, leading to the distinctive EBS patients intraepidermal blisters formation. Whilst viral mediated addition of a corrected copy of the altered gene is the ascertained approach to tackle recessively inherited EB (such as Junctional and Dystrophic EB), a potential successful combined cell and gene therapy for EBS dominant forms requires the editing of the mutated gene. In this case study, we outlined an allele specific CRISPR/Cas9 gene editing approach able to specifically detect and disrupt a de novo monoallelic c.475/495del21 mutation within exon 1 of KRT14. Taking advantage of the tailored CRISPR/Cas9 system to induce a NHEJ mediated frameshift mutations introduction, we attained a remarkable mutant allele knock-out efficiency. Following KRT14 mutant allele specific gene editing, patient derived primary keratinocytes (EBS01) restored a normal intermediate filament network and mechanical stress resilience.
2023-12-06 | GSE246343 | GEO
Project description:Epidermolysis Bullosa Simplex (EBS) is the most common form of Epidermolysis Bullosa (EB) and it is mainly inherited in an autosomal dominant manner (prevalence 1/30000 – 1/50000). Several clinical variants have been described based on the mutated gene, the site of blister formation and the anatomical distribution, but the vast majority of the patients display dominant mutations in genes encoding keratin 5 (KRT5) and keratin 14 (KRT14). The lack of functional keratin intermediate filaments causes basal keratinocytes to exhibit a dramatic cytoplasmatic softening and rupture, when subjected to minor mechanical traction, leading to the distinctive EBS patients intraepidermal blisters formation. Whilst viral mediated addition of a corrected copy of the altered gene is the ascertained approach to tackle recessively inherited EB (such as Junctional and Dystrophic EB), a potential successful combined cell and gene therapy for EBS dominant forms requires the editing of the mutated gene. In this case study, we outlined an allele specific CRISPR/Cas9 gene editing approach able to specifically detect and disrupt a de novo monoallelic c.475/495del21 mutation within exon 1 of KRT14. Taking advantage of the tailored CRISPR/Cas9 system to induce a NHEJ mediated frameshift mutations introduction, we attained a remarkable mutant allele knock-out efficiency. Following KRT14 mutant allele specific gene editing, patient derived primary keratinocytes (EBS01) restored a normal intermediate filament network and mechanical stress resilience.
2023-12-06 | GSE221645 | GEO
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
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
Project description:WGS of Mouton Vendéen sheep with Epidermolysis Bullosa
| PRJEB37460 | ENA
Project description:The goal of this study is to discover fibroblast subpopulations relevant to recessive dystrophic epidermolysis bullosa
2018-04-01 | GSE108849 | GEO