Role of the peptidase endothelin-converting enzyme-1 (ECE-1) in neurogenic inflammation, puritus and pain

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The bidirectional communication between skin cells and the peripheral nerve system (PNS) is important for regulatory processes in the skin, as pathophysiological conditions results in skin diseases, atopic dermatitis, urticaria or prurigo, for example. Activation of nociceptive nerve fibers leads to the release of neuropeptides from peripheral nerve endings, which mediate inflammation, itch, and pain by activating their corresponding G protein-coupled receptors (GPCR). For instance, the neuropeptide Substance P (SP) is directly involved in pain and inflammation by activating the neurokinin-1 receptor (NK1R). An important aspect of neuropeptide-mediated function is the interaction of the neuropeptide with its corresponding receptor and the controlling peptidase. Recently we presented the important role of the peptidase endothelin-converting enzyme-1 (ECE-1) for the regulation of certain neuropeptide receptors. This mechanism is not only important for receptor resensitization but also for intracellular signalling pathways (e.g. MAP kinases) in the cell. The aim of my project at the UCSF in San Francisco will be to test if ECE-1 is an important regulator of inflammation, pruritus or pain. Therefore, the aims of my study are 1) to analyze the expression and distribution of ECE-1, SP and NK1R in chronic inflammatory skin diseases, 2) to study the role of ECE-1 and NK1R on cell signalling events that are involved in neurogenic inflammation in vitro, and 3) investigate the role of ECE-1 and neuropeptide receptors in neurogenic inflammation and pain mouse models in vivo.