Vascular Ehlers-Danlos syndrome dermal fibroblasts’ transcriptome: pathomechanisms and targetable molecules

Vascular Ehlers-Danlos syndrome (vEDS) is a dominant inherited connective tissue disorder caused by mutations in the COL3A1 gene that encodes type III collagen (COLLIII), which is the major expressed collagen in blood vessels and hollow organs, thus explaining why its reduction due to COL3A1 mutations leads to increased bruising, arterial and bowel rupture, and uterine, cervical, and vaginal fragility during pregnancy and delivery. Although it is known that reduced amounts of COLLIII cause loss of connective tissue structural integrity, the molecular mechanisms contributing to the vEDS etiopathogenesis are poorly studied. This project aims to fill the gap in the knowledge of the vEDS pathophysiological basis. From a scientific point of view, the proposed research is innovative, since for the first time the global RNA expression profile (transcriptome) both of protein-coding genes (mRNA) and non-protein-coding genes (lncRNA and miRNA) will be analyzed on a large cohort of vEDS and control dermal fibroblasts using next generation sequencing technology (RNA-seq). This approach will provide the first large-scale investigation of gene expression alterations expected to unveil different molecular networks and biological processes related to the pathomechanisms of this multisystemic connective tissue disorder. In perspective, our study may offer significant insights not only for the elucidation of the underlying pathobiology but also for the discovery of significant disease-associated biomolecules, thus encouraging future research aimed at identification of more effective therapeutic strategies for vEDS patients’ management.