内皮微粒携带lncRNA NEAT1调控JNK/NLRP3促进巨噬细胞M1极化在 aGVHD的作用

The pathogenesis of acute graft-versus-host disease (aGVHD) is the focus of current allogeneic hematopoietic stem cell transplantation （allo-HSCT） field. Recent studies revealed that endothelial microparticles and macrophage polarization could promote graft rejection, but the correlation mechanism between them remained elusive. The preliminary data showed that the expression of lncRNA NEAT1 from endothelial microparticles was remarkably elevated, which might be the pivotal cause for M1 macrophage polarization. The latest researches showed that the signal pathway of JNK/NLRP3 participated in aGVHD and promoted M1 macrophage polarization, which might be tightly modulated by lncRNA NEAT1. Therefore, combining these above researches, we propose a scientific hypothesis that lncRNA NEAT1 delivered by endothelial microparticles regulate macrophage polarization and promote aGVHD through the signal pathway of JNK/NLRP3. The project intends to systematically answer the following questions from a serial of celluar and animal experiments using gene overexpression and gene knockdown protocols:①Whether endothelial microparticles-delivered lncRNA NEAT1 promote aGVHD through regulating macrophage polarization?②Whether endothelial microparticles-delivered lncRNA NEAT1 participate in aGVHD through modulating the signal pathway of JNK/NLRP3 and promoting macrophage polarization towards M1 phenotype? This will lay a theoretical foundation for elucidation of the pathogenesis and optimization of therapeutic strategies for aGVHD.

急性移植物抗宿主病（aGVHD）发病机制是当前移植领域关注的焦点。研究表明，内皮微粒和巨噬细胞极化可促进移植排斥反应，但二者在aGVHD的关联机制尚不清楚。预实验结果发现内皮微粒中lncRNA NEAT1表达显著增高，可能是促进巨噬细胞M1型极化的关键原因。最近研究显示JNK/NLRP3通路参与aGVHD且可能促进巨噬细胞M1型极化，并可能被lncRNA NEAT1精细调控。结合上述研究，我们提出“内皮微粒携带lncRNA NEAT1通过JNK/NLRP3通路调控巨噬细胞极化促进aGVHD”这一科学假说。本项目拟从细胞及动物水平，采用基因过表达和敲除技术，系统回答下列科学问题：①内皮微粒携带lncRNA NEAT1是否通过调控巨噬细胞极化促进aGVHD？②内皮微粒携带lncRNA NEAT1是否通过JNK/NLRP3促进巨噬细胞极化？这将为阐明aGVHD发病机制和优化治疗策略奠定理论基础。

急性移植物抗宿主病（aGVHD）是异基因造血干细胞移植术后常见并发症之一，严重危及患者生命。既往研究表明内皮微粒和巨噬细胞极化可促进移植排斥反应，但二者在aGVHD的关联机制尚不清楚。我们的预实验结果发现内皮微粒中lncRNA NEAT1表达显著增高，且在aGVHD患者及小鼠的标本中得到证实。本项目的研究结果证实JNK/NLRP3通路参与aGVHD且促进巨噬细胞M1型极化，并被lncRNA NEAT1精细调控。本项目证实内皮微粒携带lncRNA NEAT1通过JNK/NLRP3通路调控巨噬细胞极化促进aGVHD。本项目从临床标本、细胞及动物水平，采用基因过表达和敲除技术，系统回答下列科学问题：①内皮微粒携带lncRNA NEAT1是否通过调控巨噬细胞极化促进aGVHD？②内皮微粒携带lncRNA NEAT1是否通过JNK/NLRP3促进巨噬细胞极化？但本项目仍存在诸多不足，对于内皮微粒携带lncRNA NEAT1调控巨噬细胞极化的深入机制仍不明确，此外，内皮微粒携带lncRNA NEAT1的特异性有待进一步深入阐述。本项目将为阐明aGVHD发病机制和优化治疗策略奠定理论基础。