It is now well established that acute and chronic pain are common, though variable, manifestations observed in individuals suffering from Ehlers-Danlos syndrome (EDS). This clinically and genetically heterogeneous group of heritable connective tissue disorders is characterized by joint hypermobility, skin fragility and generalized soft connective tissue fragility. This is caused by defects in a variety of extracellular matrix (ECM) components, including fibrillar collagens, glycoproteins and proteoglycans. The presence of chronic pain in EDS is a major source of disability and has a severe impact on daily activities, quality of life, and psychosocial functioning, leading to anxiety, depression, frustration and/or anger. Although pain is a frequent cause for seeking medical help, it is often inadequately controlled by currently used analgesics and represents an unmet medical need. Currently, the mediators and pathways initiating and maintaining pain in EDS are poorly understood and virtually unexplored. This proposal aims to assess the role of (aberrant) ECM molecules in the initiation and generation of EDS-related pain, using innovative in vitro and in vivo techniques. This will be accomplished through a unique combination of state-of-the-art technologies, equipment, resources and collaborations. The anticipated results of this proposal will pave the way for future research on EDS-related pain.