Bioinformatic Strategy to Identify HUB Genes and Potential Drug Repurposing in Epidermolysis Bullosa

Background: Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited blistering skin disease caused by biallelic mutations in the COL۷A۱ gene, which encodes type VII collagen, an important component of the anchoring fibrils at the dermal epidermal interface. Hereditary epidermolysis bullosa (EB) is associated with blistering of the skin, formation of difficult-to-heal wounds, and severe scarring. Therefore, a great unmet need exists to improve and accelerate wound healing. Here, we performed transcriptomic analysis of the RDEB GEO dataset to discover new therapeutic targets.Method: Gene expression and miRNA datasets were obtained by searching the GEO database. Studies using a high-throughput dataset examine normal keratinocytes and RDEB as well as skin biopsies from the edges of chronic RDEB wounds compared to normal skin. To identify differentially expressed genes (DEGs), eligible gene expression profiles were investigated using the GO۲R package, |LogFc|>۱, and adj.P.value<۰.۰۵. To create and analyze the protein-protein interaction networks, STRING (۱۲.۰) and Cytoscape software (Cytohubba and MCODE plugin) were applied. The DAVID database was used for finding significant molecular pathways, gene ontology, and enrichment analysis. Finally, the drug repurposing database CLUE (https://clue.io/, accessed on ۱۶ July ۲۰۲۲) was used to identify FDA-approved drugs for potential repurposing and drug-hub Gene Interaction.Results: Based on the DEGs identified in the GSE۱۳۰۷۶۷ dataset, hsa-miR-۳۶۶۳-۳p and hsa-miR-۱۰a-۵p are differentially expressed between normal and RDEB keratinocytes, making them potential therapeutic targets. The most important HUB genes in EBDR wounds compared to healthy wounds are CXCL۸, MMP۹, TLR۴, IL۶, IL۱B, EGFR, and CXCR۴, which are involved in the inflammatory response, extracellular organization, cell adhesion, regulation of nitric oxide synthase activity, regulation of ERK ۱ and ۲, MAP kinase activity, regulation of TNF activity, Immune response and Angiogenesis. Loss of function of some of these genes is a promising candidate for preventing nonhealing wounds in patients with epidermolysis bullosa. We found ۹ hub genes out of ۲۵ key genes against which ۷۷ drug candidates could be targeted, with Ibudilast having the same inhibitory effect on three of them; IL۶, IL۱B, and TLR۴.Conclusions: Our results confirmed that the Ibudilast, hsa-miR-۳۶۶۳-۳p, and hsa-miR-۱۰a-۵p can alter the inflammation and fibrosis-like microe

کلیدواژه ها:

epidermolysis bullosa ، inflammation ، chronic wound ، GEO database