Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of human affected and unaffected skin of 4 psoriatic patients and normal skin of 3 psoriasis free individuals to reveal a complex regulation of molecular stress and immune gene responses

ABSTRACT: Gene expression profiling was performed on biopsies of affected and unaffected psoriatic skin and normal skin from seven Japanese patients to obtain insights into the pathways that control this disease. U95A Affymetrix DNA chips that contain oligonucleotide arrays of approximately 12,000 well-characterized human genes were used in the study. The statistical analysis of the Affymetrix data, based on the ranking of the Student-test statistic, revealed a complex regulation of molecular stress and immune gene responses. The majority of the 266 induced-genes in affected and unaffected psoriatic skin were involved with interferon mediation, immunity, cell-adhesion, cytoskeleton restructuring, protein trafficking and degradation, RNA regulation and degradation, signaling transduction, apoptosis and atypical epidermal cellular proliferation and differentiation. The disturbances in the normal protein degradation equilibrium of skin were reflected by the significant increase in the gene expression of various protease inhibitors and proteinases including the induced components of the ATP/ubiquitin-dependent non-lysosomal proteolytic pathway that is involved with peptide processing and presentation to T-cells. Some of the upregulated genes, such as TGM1, IVL, CSTA, FABP5 and SPRR, are well known psoriatic markers involved in atypical epidermal cellular organization and differentiation. In the comparison between the affected and unaffected psoriatic skin, the transcription factor JUNB was found at the top of the statistical rankings for the 51 significantly upregulated genes in affected skin, suggesting that it has an important but as yet undefined role in psoriasis. Our gene expression data and analysis suggest that psoriasis is a chronic IFN and T-cell-mediated immune disease of the skin where the imbalance in epidermal cellular structure, growth and differentiation arises from the molecular antiviral stress signals initiating inappropriate immune responses. Experiment Overall Design: Analysis of the expression profile of skin samples for each of three conditions (states) of psoriasis activity Experiment Overall Design: 3 samples were from psoriasis negative individuals (biological replicates) Experiment Overall Design: 4 samples were from psorasis free skin areas of psoriasis active individuals (biological replicates) Experiment Overall Design: 4 samples were from psorasis active skin areas of psoriasis active individuals (biological replicates)

ORGANISM(S): Homo sapiens

DISEASE(S): psoriasis vulgaris

SUBMITTER: William Kenworthy

PROVIDER: E-GEOD-2737 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Gene expression profiling of Japanese psoriatic skin reveals an increased activity in molecular stress and immune response signals.

Kulski Jerzy K JK Kenworthy William W Bellgard Matthew M Taplin Ross R Okamoto Koichi K Oka Akira A Mabuchi Tomotaka T Ozawa Akira A Tamiya Gen G Inoko Hidetoshi H

Journal of molecular medicine (Berlin, Germany) 20051111 12

Gene expression profiling was performed on biopsies of affected and unaffected psoriatic skin and normal skin from seven Japanese patients to obtain insights into the pathways that control this disease. HUG95A Affymetrix DNA chips that contained oligonucleotide arrays of approximately 12,000 well-characterized human genes were used in the study. The statistical analysis of the Affymetrix data, based on the ranking of the Student t-test statistic, revealed a complex regulation of molecular stress ...[more]

PMID: 16283139

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Project description:Gene expression profiling was performed on biopsies of affected and unaffected psoriatic skin and normal skin from seven Japanese patients to obtain insights into the pathways that control this disease. U95A Affymetrix DNA chips that contain oligonucleotide arrays of approximately 12,000 well-characterized human genes were used in the study. The statistical analysis of the Affymetrix data, based on the ranking of the Student-test statistic, revealed a complex regulation of molecular stress and immune gene responses. The majority of the 266 induced-genes in affected and unaffected psoriatic skin were involved with interferon mediation, immunity, cell-adhesion, cytoskeleton restructuring, protein trafficking and degradation, RNA regulation and degradation, signaling transduction, apoptosis and atypical epidermal cellular proliferation and differentiation. The disturbances in the normal protein degradation equilibrium of skin were reflected by the significant increase in the gene expression of various protease inhibitors and proteinases including the induced components of the ATP/ubiquitin-dependent non-lysosomal proteolytic pathway that is involved with peptide processing and presentation to T-cells. Some of the upregulated genes, such as TGM1, IVL, CSTA, FABP5 and SPRR, are well known psoriatic markers involved in atypical epidermal cellular organization and differentiation. In the comparison between the affected and unaffected psoriatic skin, the transcription factor JUNB was found at the top of the statistical rankings for the 51 significantly upregulated genes in affected skin, suggesting that it has an important but as yet undefined role in psoriasis. Our gene expression data and analysis suggest that psoriasis is a chronic IFN and T-cell-mediated immune disease of the skin where the imbalance in epidermal cellular structure, growth and differentiation arises from the molecular antiviral stress signals initiating inappropriate immune responses. Keywords: Disease State Analysis

Project description:Background: Plaque psoriasis is a chronic autoimmune disorder characterized by the development of red scaly plaques. To date psoriasis lesional skin transcriptome has been extensively studied, whereas only few proteomic studies of psoriatic skin are available. Aim: The aim of this study was to compare protein expression patterns of lesional and normally looking skin of psoriasis patients with skin of the healthy volunteers, reveal differentially expressed proteins and identify changes in cell metabolism caused by the disease. Methods: Skin samples of normally looking and lesional skin donated by psoriasis patients (n = 5) and samples of healthy skin donated by volunteers (n = 5) were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). After protein identification and data processing, the set of differentially expressed proteins was subjected to protein ontology analysis to characterize changes in biological processes, cell components and molecular functions in the patients' skin compared to skin of the healthy volunteers. Results: The performed analysis identified 405 and 59 differentially expressed proteins in lesional and normally looking psoriatic skin compared to healthy control. We discovered decreased expression of KNG1, APOE, HRG, THBS1 and PLG in normally looking skin of the patients. Presumably, these changes were needed to protect the epidermis from spontaneous activation of kallikrein-kinin system and delay the following development of inflammatory response. In lesional skin, we identified several large groups of proteins with coordinated expression. Mainly, these proteins were involved in different aspects of protein and RNA metabolism, namely ATP synthesis and consumption; intracellular trafficking of membrane-bound vesicles, pre-RNA processing, translation, chaperoning and degradation in proteasomes/immunoproteasomes. Conclusion: Our findings explain the molecular basis of metabolic changes caused by disease in skin lesions, such as faster cell turnover and higher metabolic rate. They also indicate on downregulation of kallikrein-kinin system in normally looking skin of the patients that would be needed to delay exacerbation of the disease.

Project description:Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional profiling is used to compare gene expression patterns manifested by human psoriatic skin lesions with those that occur in five psoriasis mouse models (K5-Tie2, imiquimod, K14-AREG, K5-Stat3C and K5-TGFbeta1). While the cutaneous gene expression profiles associated with each mouse phenotype exhibited statistically significant similarity to the expression profile of psoriasis in humans, each model displayed distinctive sets of similarities and differences in comparison to human psoriasis. For all five models, correspondence to the human disease was strong with respect to genes involved in epidermal development and keratinization. Immune and inflammation-associated gene expression, in contrast, was more variable between models as compared to the human disease. These findings support the value of all five models as research tools, each with identifiable areas of convergence to and divergence from the human disease. Additionally, the approach used in this paper provides an objective and quantitative method for evaluation of proposed mouse models of psoriasis, which can be strategically applied in future studies to score strengths of mouse phenotypes relative to specific aspects of human psoriasis. Global transcriptional profiling was utilized to evaluate the similarity between human psoriasis and the psoriasis-like phenotypes that develop in five mouse models (K5-Tie2, IMQ, K14-AREG, K5-Stat3C, K5-TGFbeta1) Expression patterns associated with mouse phenotypes were evaluated by comparing lesional skin from transgenic or IMQ-treated mice (n = 2-3) with normal skin obtained from control mice (n = 2-3).

Project description:<p>Psoriasis, a highly prevalent disease of humans of unknown cause, is a chronic inflammatory disorder primarily involving skin, with distinctive clinical characteristics. With the newly developed tools that facilitate microbiome research, it now is possible to assess whether the cutaneous microbiome plays a role in the pathogenesis of this disorder. Preliminary data from our studies suggest that the cutaneous microbiome in psoriasis is complex and possibly different from normal. To deal with this complexity, we propose to examine the cutaneous microbiome in relation to psoriasis with explorations at several taxonomic and informatic levels. Our overall objective is to examine how changes in the normal cutaneous microbiome contribute to the pathogenesis of psoriasis. Since causality is complex and often difficult to prove, and beyond the scope of this RFP, our overall hypothesis is that there are alterations in the cutaneous microbiome in areas of skin affected by psoriasis in comparison with the range observed in clinically unaffected areas, or in healthy persons. We also hypothesize that the characteristics of the microbiome may affect clinical responses to the immunomodulatory agents used to treat psoriasis. An alternative hypothesis is that effective treatment of psoriasis with systemic immunomodulatory agents will not substantially affect the disordered microbial ecosystem. Such observations would provide evidence for the roles of the microbiota in this disorder. Since an important consideration in microbiome research is the optimal level (e.g. phylum, genus, species, strain, gene) at which to examine a scientific question, and we are not yet certain what are the optimal levels for psoriasis, this also will be examined. Our studies of psoriasis should allow development of both approaches and tools that will have general utility for Microbiome research. To test our hypothesis, we propose the following specific aims: 1) To understand the cutaneous microbiome species composition overlaying psoriatic lesions; 2)To investigate differences in metagenome content for psoriatic lesions compared to normal skin; 3) To identify differences in the transcriptional profiles of the microbiome and the host between normal skin and psoriatic lesions using high-throughput sequencing; and 4) To estimate the effects of systemic immunomodulatory therapy for psoriasis on microbiome composition. In total, these studies should help us understand the role of the microbiome in psoriasis pathogenesis.</p> <p>We sought to characterize and compare the cutaneous microbiota of psoriatic lesions (lesion), unaffected contralateral skin from psoriatic patients (normal), and similar skin loci in matched healthy controls (control) in order to discern patterns that govern skin colonization and their relationship to clinical diagnosis. Using high-throughput 16S rRNA sequencing, we assayed the cutaneous bacterial communities of 51 matched triplets and characterized these samples using community data analysis techniques.</p>

Dataset Information

Transcription profiling of human affected and unaffected skin of 4 psoriatic patients and normal skin of 3 psoriasis free individuals to reveal a complex regulation of molecular stress and immune gene responses

Publications

Gene expression profiling of Japanese psoriatic skin reveals an increased activity in molecular stress and immune response signals.

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