HIF-2α经SOCS1 m6A甲基化修饰调控Kupffer细胞向M2型极化减轻肝移植缺血/再灌注损伤的机制研究

缺血期的特殊微环境是导致肝移植后供体源巨噬细胞(KCs)向M2型极化、拮抗肝移植缺血/再灌注损伤(I/RI)的重要原因。机体应对缺血所产生的缺氧诱导因子2α（HIF-2α）富集于肝脏，生物信息学分析提示它很可能是促使KCs向M2型极化的关键驱动因子。诱导m6A甲基化修饰是HIF-2α实现其功能的重要调控手段，而对SOCS1/STAT1通路的m6A修饰是调控KCs表型的重要途径，我们根据预实验结果推测：HIF-2α可通过诱导甲基化酶Mettl3以及YTHDF1的高表达，介导SOCS1 m6A修饰，最终促使KCs向M2型极化。据此，本项目将从细胞及动物活体角度，通过定点突变等技术，深入探索HIF-2α通过m6A修饰调控KCs极化信号的具体方式，以期揭示供体源KCs向M2型极化的相关机制，为防治肝移植I/RI提供新的理论思路和实验靶点。

The special microenvironment during the ischemic period is an important factor leading to the polarization of donor-derived macrophages (KCs) to M2 type after liver transplantation, which antagonizes the ischemia / reperfusion injury (I/RI) in liver transplantation. The body's response to ischemia-induced hypoxia-inducible factor 2α (HIF-2α) is rich in the liver, and bioinformatics analysis suggests that it may be a key driver for the polarization of KCs to M2 type. Induction of m6A methylation modification is an important regulatory means for HIF-2α to achieve its function, and m6A modification of SOCS1/ STAT1 pathway is an important way to regulate the phenotype of KCs. We speculate from the preliminary experimental results: by inducing the high expression of methylation enzymes Mettl3 and YTHDF1, HIF-2α can mediate SOCS1 m6A modification, and finally promote KCs to M2 type polarization. Based on this, this project will explore the specific ways in which HIF-2α modifies the KCs polarization signal through m6A modification from the perspective of cells and animals, through site-directed mutagenesis, etc., with a view to revealing the mechanism related to M2 type polarization from donor-derived KCs, providing new theoretical ideas and experimental targets for the prevention and treatment of liver transplantation I/RI.