FFAR4介导ω-3长链多不饱和脂肪酸调控大黄鱼炎症反应的机制研究

ω-3长链多不饱和脂肪酸（ω-3 LC-PUFA）可抑制海水鱼的炎症反应，但免疫细胞如何识别脂肪酸并调控症性反应的机制仍然不明。游离脂肪酸受体4（FFAR4）是哺乳动物中重要的脂肪酸识别受体，但在鱼类中尚未见报道。申请人前期研究已证实大黄鱼中存在FFAR4，且可响应脂肪酸刺激影响下游炎症基因表达。在此基础上本项目拟选取我国重要的海水养殖鱼类—大黄鱼为研究对象，围绕“FFAR4如何介导ω-3 LC-PUFA调控炎症反应”这一科学问题开展以下工作：（1）阐明FFAR4基因和蛋白在大黄鱼巨噬细胞中的空间表达特征；（2）解析大黄鱼FFAR4激活和其所介导的信号传导模式；（3）运用基因沉默和过表达技术，在离体和在体条件下阐明FFAR4介导ω-3 LC-PUFA发挥调控炎症反应的作用。本项目的实施，将进一步揭示ω-3 LC-PUFA调控海水鱼类炎症反应的机制，为优化海水鱼饲料配方提供理论支撑。

Omega-3 long-chain polyunsaturated fatty acids (ω-3 LC-PUFAs) can significantly reduce the inflammatory response in marine fish, whereas the mechanism of how immune cells sense free fatty acids and modulate inflammatory responses remains to be defined. In mammals, free fatty acid receptor 4 (FFAR4) has been reported to emerge as one of the fatty acid receptors that could sense fatty acids, however, no related evidence has been reported in fish. We found that large yellow croaker FFAR4 (LcFFAR4) could respond to fatty acids and play a role in signaling transduction and expression of inflammatory genes. Based on those, we will (1) locate the mRNA and protein expression of FFAR4 in macrophages of large yellow croaker by in situ hybridization and immunohistochemistry; (2) analyze the activation pattern of LcFFAR4 and characteristics of mediated signaling transduction; (3) clarify the function of FFAR4 in ω-3 LC-PUFAs-modulated fish inflammatory responses both in vitro and in vivo through overexpression and knock-down studies. This project will reveal the FFAR4-mediated mechanism of ω-3 LC-PUFAs in regulating inflammatory responses, and contribute to the diet development for marine fish.