GPCR-TRP信号轴介导的蝎子毒液多肽IP致痒作用与机制及抗瘙痒研究

瘙痒尤其慢性瘙痒是一种危害严重的皮肤病症，影响全球约五分之一的人口，广泛困扰人们的生活。目前，瘙痒发生的病理机制十分复杂且不清楚，临床上也无特异性抗瘙痒治疗药物。项目前期发现皮下注射蝎子毒液多肽IP在小鼠的脸颊能浓度依赖地诱导小鼠产生抓挠的瘙痒行为，且IP多肽能有效激活小鼠外周神经元的胞外钙内流。本项目围绕蝎子毒液多肽IP致痒的分子、细胞和神经信号传递机制的关键科学问题，拟开展：细胞和动物水平上蝎子毒液多肽IP作用外周神经元细胞膜痒受体的鉴定；蝎子毒液多肽IP作用DRG细胞膜痒受体的下游偶联离子通道的阐明，抗瘙痒膜蛋白/离子通道靶点及其候选药物分子的发现与确证。这些工作将揭示蝎子蛰刺甚至毒液动物叮咬诱导瘙痒的病理现象及其分子、细胞和神经信号传递机制，鉴定抗瘙痒膜蛋白/离子通道新靶点，诠释蝎子乃至动物毒液多肽在痒觉神经生物学及抗瘙痒研究中的贡献，为研发新型、特异和高效的止痒药物奠定科学基础。

Itching, especially chronic itching, is a serious skin disease that affects about one fifth of the world's population and is a widespread problem for people's quality of life. Due to the complicated and unclear molecular mechanism of pruritus pathogenesis, there are still no specific anti-itch drugs in clinical practice. In the early stage of this project, we was found that the subcutaneous injection of scorpion venom peptide IP on the cheeks of mice could dose-dependently induce the scratching of mice, and that the scorpion venom peptide IP effectively activated extracellular calcium influx in peripheral neurons of mice. This project will focus on the key scientific question on the molecular and cellular mechanisms of the scorpion venom peptide IP-induced itchy signal transmission and then will investigate the following parts: 1) In vitro and in vivo identification of itch receptors on peripheral neuronal membranes targeted by the scorpion venom peptide IP; 2) Clarification of downstream ion channels coupled by itch receptors on peripheral neuronal membranes targeted by the scorpion venom peptide IP; 3) Discovery and confirmation of antipruritic membrane protein/ion channel new targets and the related candidate drug molecules. These works will reveal the pathological phenomenon of scorpion sting and even animal bite-induced itching and related molecular/cellular signaling mechanism, identify new anti-pruritic targets of membrane proteins/ion channels, and interpret the molecular probe contribution of scorpion even animal venom peptides during the investigation of itch neurobiology and anti-pruritic research, which lay a scientific and technical foundation for the research and development of new, specific and efficient antipruritic drugs.