MicroRNAs in dystrophic epidermolysis bullosa fibrosis: expression profiling, activity and therapeutic perspectivesOngoing
|Project lead||Dr. Giovanna Zambruno|
|Organisation||Bambino Gesù Children’s Hospital, IRCCS, Rome|
|Partner organizations & collaborators||Co-investigators: Dr Teresa Odorisio, Laboratory of Molecular and Cell Biology, IDI-IRCCS, Rome, Italy|
Collaborator: Professor Leena Bruckner-Tuderman, Universitätsklinikum Freiburg – Hautklinik, Germany
|Project budget||EUR 196,500.00|
|Start date / Duration||01. Mar 2020 / 36 months|
|Funder(s) / Co-Funder(s)||DEBRA UK, DEBRA Austria, DEBRA Spain, MSAP/EBEP Reviewed|
|Research area||Skin cancer & fibrosis, EB genetics, epigenetics & biology|
Short lay summary
Our DNA is made-up of genes that store the information to build proteins that form our body. The DNA instructions are transcribed into RNA molecules called messenger RNAs (mRNAs), which serve to produce these proteins (translation). However, some RNAs, called non-coding RNAs, are not translated into proteins but regulate the amount of proteins produced. MicroRNAs (miRNAs) are non-coding RNAs that block protein production by interacting with specific mRNAs. MiRNAs are key regulators of all biological processes and their abnormal function contributes to many diseases, including fibrotic (scarring) skin disorders.
In recessive dystrophic epidermolysis bullosa (RDEB) unremitting blistering leads to severe fibrosis that plays an important role in the development of the most severe disease complications. This research group has observed that some miRNAs are more abundant in fibroblasts from RDEB patients (RDEBFs) and exert a pro-fibrotic activity in vitro. Based on these preliminary studies, the present project aims at identifying additional miRNAs dysregulated in RDEBFs and at characterizing their role in key fibrotic processes such as the production and release of important pro-fibrotic molecules (e.g. the transforming growth factor-b1) and the dermal (skin) stiffening.
Recessive dystrophic epidermolysis bullosa (RDEB) is caused by mutations in the COL7A1 gene encoding type VII collagen (Col7), which ensures epidermal-dermal adhesion. RDEB hallmarks are skin fragility, unremitting blistering, and defective wound healing with inflammation and fibrosis. Fibrosis underlies most severe disease complications, and contrasting it represents a strategy to counteract disease progression. MicroRNAs (miRNAs) are non-coding RNAs acting as negative regulators of gene expression in health and disease, including fibrosis. miRNA expression profiles and function have been investigated in two skin disease models of altered wound healing with fibrosis, hypertrophic scars and keloids. On the other hand, the role of miRNAs in RDEB fibrosis is almost unexplored. In a preliminary study, we identified a miRNA, miR-145-5p, overexpressed in skin fibroblasts from RDEB patients (RDEBFs) where it exerts a pro-fibrotic function. In RDEBFs, miR-145-5p inhibition determines the reduction of contractile markers (α-SMA, transgelin) and of jagged 1 (JAG1), a Notch signalling member and an inducer of fibrosis. In addition, we found that JAG1 is over-expressed and the Notch signalling cascade activated in RDEBFs, thus identifying a novel pro-fibrotic and druggable pathway activated in RDEB. Based on our preliminary data, we hypothesize that: (i) miRNAs exert a role in injury-driven fibrosis of RDEB, and (ii) deregulated miRNAs and their targets can be exploited for the design of novel therapeutic approaches to limit RDEB fibrosis. Specific aims of the research proposal are: 1. to identify miRNAs deregulated in fibroblasts from RDEB patients throughout a high-throughput screening; 2. to characterize miRNAs contribution to fibrosis in RDEB patients by functional assays and investigation of expression levels of miRNA targets and known fibrosis markers; 3. to identify novel druggable molecules among deregulated miRNAs, their targets and related molecular networks and validate their function in RDEB.
This research project expects to identify novel miRNAs/miRNA targets involved in fibrosis, which (i) can contribute to the definition of a RDEB “fibrosis signature”, and (ii) may represent innovative therapeutic tools and/or therapeutic targets to counteract RDEB fibrosis and disease progression. In parallel, researchers point to exploit knowledge about deregulated miRNAs as picklock to unveil disease pathomechanisms and novel druggable pathways.