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

皮肤细胞和周围神经系统(PNS)之间的双向通讯对皮肤的调节过程非常重要，因为病理生理条件会导致皮肤病，例如特应性皮炎、荨麻疹或瘙痒。伤害性神经纤维的激活导致周围神经末梢释放神经肽，神经肽通过激活相应的G蛋白偶联受体(GPCR)而介导炎症、瘙痒和疼痛。例如，神经肽P物质(SP)通过激活神经激肽-1受体(NK1R)直接参与疼痛和炎症。神经肽介导的功能的一个重要方面是神经肽与其相应的受体和控制肽酶的相互作用。最近，我们提出了内皮素转换酶-1在某些神经肽受体调节中的重要作用。这一机制不仅对受体的再敏化很重要，而且对细胞内的信号通路(如MAP激酶)也很重要。我在旧金山加州大学旧金山分校的这个项目的目的将是测试ECA-1是否是炎症、瘙痒或疼痛的重要调节因子。因此，本研究的目的是：1)分析ECE1、SP和NK1R在慢性炎症性皮肤病中的表达和分布；2)研究ECE1和NK1R在体外参与神经源性炎症的细胞信号转导事件中的作用；3)探讨ECE1和神经肽受体在体内神经源性炎症和疼痛小鼠模型中的作用。

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.