鞘脂是细胞膜“脂筏”结构的重要组分，部分鞘脂分子对TRP通道的开放闭合产生影响，其机制不明。我们发现，外源鞘脂可被人体吸收并调节内源性鞘脂的代谢（2016 JAFC）；鞘脂比例对细胞膜是否成型极为关键（2014 Biophys J）。我们又发现，细胞膜脂质与TRP通道的关键功能性区域紧密结合并形成氢键（2018 PNAS两篇和Nat Commun）。我们推测，不同鞘脂成分对TRP通道存在差异性的调节作用和机制。本课题拟1)优化鞘脂组学分析方法、建立靶向调节鞘脂代谢的细胞模型、通过膜片钳记录检测脂质体和细胞膜TRPM4/7通道的电流，明确对TRPM4/7通道的激活或抑制作用较大的鞘脂组分。2)通过分子生物学信号通路检测，结合电镜观测TRP通道鞘脂复合物精密结构和“脂筏”结构变化，深入探讨鞘脂代谢的动态过程对TRP离子通道功能影响的分子机制。该项目对理解细胞膜脂质和蛋白的交互关系意义重大。

Sphingolipids are critical components of “lipid rafts”. Some sphingolipids regulate the opening and close of TRP channels with unknown mechanism. We have found that exogenous sphingolipids can be partially absorbed thus affect the synthesis and metabolism of endogenous sphingolipids (2016 JAFC). As the composition of sphingolipids modifying, the physical and chemical properties of plasma membranes dramatically variated （2014 Biophys J）. Along with analyzing structures of TRP channels, we found membrane lipids directly binding to the key amino acid residues in functional domains of TRP channels with forming hydrogen bonds and other interactions (2018 PNAS a,b and Nat Commun). We speculate that different type of sphingolipids may have different regulatory effects and mechanisms on TRP channels. Here we propose the investigation about the regulatory effects of sphingolipids on TRPM4 and TRPM7 channels under sphingolipids’ dynamic metabolism. This project aims to 1) optimize the methods of sphingolipidomics, establish several cell models targeting the regulation of sphingolipid metabolism, and patch clamp recording the current of TRPM4/7 channels on liposomes and cell membranes, to identify the components of sphingolipids that are potent activators or inhibitors of TRPM4/7; 2) observe the complex structure of sphingolipids with TRP channel and “lipid rafts” , combining with molecular signaling pathway analysis to elucidate the molecular mechanisms. Our study would impact on the understanding on plasma membrane and the lipids-protein interactions.