DNA damage response (DDR) mechanisms - in particular PARP1 signaling - are suggested to be important in the emergence of soft tissue mineralization (STM). A hallmark STM disorder is pseudoxanthoma elasticum (PXE), caused by mutations in the liver transporter ABCC6, with a complex and incompletely understood pathogenesis. Several dysregulated mediators in PXE show remarkable resemblance with PARP1 signaling cascades; our preliminary data show activated PARP1 signaling in PXE patients, reduced mineralization in vitro and in vivo after PARP inhibition, and identify miR-204 as a regulator. Now, we will perform a more profound study of the pathophysiological role of PARP1 signaling in PXE and evaluate its use as a biomarker and therapeutic target for this intractable disease. First, we will study the mechanisms involved in activating the DDR/PARP1 cascade in PXE fibroblasts and the regulatory role of miRNAs. Second, we will evaluate possible correlations between PARP1 activity, circulating miRNAs and PARP1-related genomic variants and the clinical severity of PXE. Finally, we will evaluate several known PARP1 inhibitors as potential treatment in PXE, using in vitro and in vivo models. Taken together, this project will lead to major advances in the complex pathogenesis of PXE, will delineate non-invasive (miRNA) biomarkers for the disease and will lead to novel therapies by drug-repurposing for this disorder. As such it will significantly improve patient management and treatment.