酸敏感离子通道在皮肤瘙痒中的作用及其机制

Pruritus is one of the important symptoms in numerous skin diseases and systematic diseases, and about four percent of the population in the world suffer from pruritus every year. Recently more attentions have been paid to the discovery of the mechanisms of pruritus. Pruritus always happens along with tissue inflammation, and the process of inflammation will lead to extracellular pH decrease, which can activate a series of ion channels including acid-sening ion channels (ASICs). Pruritus has many similarities with pain in transduction pathway, transmission mediators and so on. ASICs are expressed in sensory neurons and play critical roles in pain, however, it is still unknown if ASICs take part in the process of pruritus. In light of previous research findings and our preliminary experiment results, we make a hypothesis that stimulators increase the expression of NGF, which up-regulates the expression and function of ASICs and the activation of ASICs leads to membrane potential depolarization and improved release of substance P, at last pruritus occurs. Taking advantage of knockout mice, the proposed study will investigate the effect and mechanisms of ASICs in pruritus, with application of molecular biology techniques, immunofluorescence, whole-cell patch-clamp and microdialysis test. Our study will provide a new candidate for the elucidation of mechanisms of pruritus and the therapy of related diseases.

瘙痒是多种皮肤病和系统性疾病的重要症状之一，全球每年约有4%的人口遭受瘙痒的折磨。近年来关于瘙痒发病机制的研究越来越受到关注，瘙痒往往伴随炎症的产生，而炎症过程常常发生胞外pH值下降，酸化的外液可以激活一系列离子通道其中包括酸敏感离子通道（ASICs）。瘙痒与疼痛在传导通路、传递介质等诸多方面存在相似处，而表达于感觉神经元并在疼痛中发挥重要作用的酸敏感离子通道是否参与瘙痒过程，目前仍未见报道。根据前人研究成果和本课题组的预实验结果，我们提出假设：致痒刺激引起NGF表达增加，进而上调ASICs的表达和功能，ASICs通道开放后一方面细胞膜去极化神经元兴奋性增加，一方面促进P物质的释放，最终引起瘙痒反应。本项目拟综合运用分子生物学、免疫荧光、全细胞膜片钳、在体微透析检测等技术，利用基因敲除小鼠，探讨酸敏感离子通道在瘙痒中的作用及其机制，以期为瘙痒发病机制的阐明和瘙痒的治疗提供新的思路。

瘙痒，是指由特定因素引起搔抓欲望或搔抓反射的不愉快感受，是多种皮肤病和系统性疾病中重要的症状之一。近年来关于瘙痒发病机制的研究成为新的热点。酸敏感离子通道（ASICs）是一类由质子门控的、非电压依赖的阳离子通道，广泛表达于中枢和外周神经系统。DRG在伤害性感知中具有重要作用，并主要表达ASIC1a和ASIC3亚基。本项目研究发现质子本身不会引起搔抓反射，但会强化氯喹引起的瘙痒。ASIC1、ASIC3在氯喹造模后DRG组织中表达均增加，但ASIC1a特异性阻断剂PcTx1不改善氯喹引起的瘙痒，而ASICs非特异性阻断剂阿米洛利及ASIC3特异性阻断剂APETx2均显著改善氯喹所致瘙痒行为。氯喹致痒刺激引起NGF表达上调，NGF作用于DRG神经元ASICs通道，促进通道开放，神经元活性增加，瘙痒传递增加；氯喹致痒刺激引起P物质表达增加，促进瘙痒反应。本研究提示ASIC3将是瘙痒发病机制中新的靶点，为抗瘙痒药物的研发提供新的思路。