TRPA1 SUMO/deSUMO化修饰在非组胺依赖性痒中的调控作用

Although the mechanism of histamine-independent itch has been intensively investigated over the past several years, it remains unclear. Our preliminary study has shown that the level of SUMO1-conjugated proteins in trigeminal ganglia tissue was markedly increased after subcutaneous injection of chloroquine pruritogen into the cheek as compared to the uninjected side. SENP1flox/flox mice were crossed with NaV1.8-Cre mice to create primary somatosensory neurons specific deletion of SENP1 mice (SENP1 cKO). SENP1 cKO mice exhibit reduced sensitivity of histamine-independent itch compared to the control mine, but not affect histamine-dependent itch. TRPA1 undergoes SUMO modification and is deSUMOylated by SENP1. Our aims are to: 1. Define the role of SUMO/deSUMO modification in histamine-independent itch. 2. Test whether TRPA1 is able to be modified by SUMO1 and regulated by SENP1. 3. Elucidate the molecular and cellular mechanisms of the TRPA1 SUMO/deSUMO modification on the histamine-independent itch. The expected result of this project will provide clear mechanistic insight into how TRPA1 SUMO/deSUMO modification regulates its gating, membrane trafficking, the interplay between TRPA1 PTMs and involving changes in nociceptive signaling events and lead to regulation of histamine-independent itch. The project will not only advance our knowledge on the underlying mechanism of itch, but also help us identify potential targets for itch treatment.

目前临床上对非组胺依赖性痒缺乏有效的治疗方法，究其原因是因为痒觉传导的具体机制尚不清楚。预实验结果表明，小鼠面颊部注射氯喹可以引起TG组织中SUMO1结合蛋白水平升高；初级感觉神经元条件性敲除SENP1小鼠表现为非组胺依赖性痒觉敏感性下调；在非组胺依赖性痒觉信号通路中关键的TRPA1受体能够被SUMO修饰，并且SENP1调控其去SUMO化。据此提出以下假说: TRPA1通过SUMO/deSUMO修饰参与非组胺依赖性痒觉调控。科学问题包括：1.确定SUMO/deSUMO修饰在非组胺依赖性痒觉中的作用；2.确定TRPA1能够被SUMO修饰并参与非组胺依赖性痒觉信号通路的调控；3.确定TRPA1 SUMO/deSUMO修饰参与非组胺依赖性痒觉调控的机制。阐明TRPA1 SUMO/deSUMO化修饰在门控、膜转运、PTMs间相互作用及其在痒觉调控中的作用和机制，对揭示痒觉传导机制具有理论价值。

目前临床上对非组胺依赖性痒缺乏有效的治疗方法，究其原因是因为痒觉传导的具体机制尚不清楚。实验结果表明， TRPA1通过SUMO/deSUMO修饰参与非组胺依赖性痒觉调控。1.确定SUMO/deSUMO修饰在非组胺依赖性痒觉中的作用；2.确定TRPA1能够被SUMO修饰并参与非组胺依赖性痒觉信号通路的调控；3.确定TRPA1 SUMO/deSUMO修饰参与非组胺依赖性痒觉调控的机制。阐明TRPA1 SUMO/deSUMO化修饰在痒觉调控中的作用和机制，对揭示痒觉传导机制具有理论价值。