m6A甲基化转移酶METTL3通过靶向SOCS2调控JAK2/STAT3/NF-κB信号通路参与哮喘气道平滑肌细胞增殖与肥大的机制研究

N6-甲基腺苷（m6A）甲基化是哺乳动物最普遍的转录后修饰方式。已有研究证实m6A甲基化转移酶METTL3在肿瘤、干细胞分化及心肌肥大中起重要作用,但是其对哮喘气道重塑的作用尚不清楚。SOCS2是METTL3的靶基因，它可以抑制JAK2/STAT3/ NF-κB信号通路调控细胞的增殖, 那么METTL3是否通过SOCS2调控JAK2/STAT3/NF-κB信号通路参与调节气道平滑肌细胞增殖肥大？本课题拟从临床样本、动物模型及细胞水平三个方面，利用临床哮喘患者气道平滑肌组织，平滑肌特异性Mettl3敲除的小鼠慢性哮喘模型以及METTL3基因干扰的气道平滑肌细胞，以meRIP-seq，激光捕获显微切割技术以及荧光素酶报告实验等方法，探讨METTL3对气道平滑肌细胞增殖肥大的影响及作用机制。本研究将从m6A甲基化这个全新的角度揭示气道重塑的发生机制，力求为临床慢性哮喘的诊治提供新的治疗靶点。

N6-Methyladenosine (m6A) methylation is the most prevalent posttranscriptional modification on mammalian mRNA. Previous studies have confirmed that the m6A methylase methyltransferase-like 3(METTL3) plays an important role in myocardial hypertrophy, but its role in airway remodeling remains unclear. Studies have confirmed that SOCS2 was the target of METTL3, and it could inhibit the JAK2/STAT3/NF-κB signaling pathway, which is involved in the regulation of cell proliferation. So whether METTL3 is involved in the regulation of proliferation and hypertrophy of airway smooth muscle cells through the regulation of JAK2/STAT3/ NF-κB signaling pathway by SOCS2? We collect the clinical asthma airway smooth muscle tissue sample and conduct the smooth muscle specific Mettl3 knockout mice model of chronic asthma and The METTL3 gene interfered airway smooth muscle cells, using meRIP - seq, laser micro cutting technology, luciferase report methods and related molecular biological experiments to explore METTL3 function and role in proliferation and hypertrophy of airway smooth muscle cells. This study will reveal the mechanism of airway remodeling from the perspective of m6A methylation, and provide a new therapeutic target for the diagnosis and treatment of clinical chronic asthma.