靶向TRPV3离子通道的吖啶酮类化合物抗瘙痒功能及机制研究

瘙痒是一种常见的皮肤科疾病，伴随着一种迫切渴望搔抓来缓解的瘙痒感受，严重的影响人们的心理健康和生活质量，目前临床上使用的药物具有用药周期长、疗效弱、副作用大、不能完全治愈等弊端，迫切需要安全有效的抗瘙痒新药。近期许多国内外科研团队和我们自己（Br J Pharmacol 2021;178:1669-1683）的研究发现，可通过抑制TRPV3离子通道而发挥显著的抗瘙痒功能。在前期工作中我们发现了一个药用植物来源、结构新颖的丫啶酮类化合物对TRPV3通道及其功能获得性突变体具有抑制作用。本项目拟研究该化合物对瘙痒动物模型的影响及作用机制，通过电生理、定点突变、结构模拟等研究手段探索其与TRPV3离子通道的结构功能关系，并在此基础进行结构与功能优化以降低毒性和提高抗瘙痒功能，希望通过本项目的研究，发现安全有效的抗瘙痒候选药物。

Itch, also known as pruritus, is a common dermatological disease which is an extremely uncomfortable skin feeling that triggers an urgent need to scratch. Itch has a profound impact on people's mental health and quality of life. Clinical therapeutic drugs has a long treatment cycle, poor anti-pruritus effect, obvious side effects, incomplete cure and many other issues. Recently, other research groups’ studies and our own study (Br J Pharmacol 2021;178:1669-1683) found that inhibiting TRPV3 ion channel can exert significant anti-pruritus function. In our previous work, we found a new acridone alkaloid compound from a medicinal plant can inhibit TRPV3 and gain-of-function mutation of TRPV3. In this proposed study, we aim at evaluating the antipruritic effects and mechanism of the acridone compound on mice with itching models. With the aid of electrophysiology, site-directed mutagenesis and structure modeling techniques, we will explore the structural and functional relationship between the compound and TRPV3 ion channel which will help us to optimize structure and function to reduce toxicity and improve anti-pruritus effects of acridone compound. We hope to find safe and effective anti-itch drug candidates.