我们通过转录组测序发现，在SM22α（转凝蛋白）敲除小鼠的血管炎症相关基因表达明显上调；这些高表达的基因均受控于NF-kB；SM22α敲除小鼠显示出增加的血管炎症。然而， SM22α与细胞炎症应答之间的相互关系尚未阐明。本项目拟从炎症信号转导入手，分别探寻炎症刺激下，血管平滑肌细胞SM22α表达水平和动态修饰变化特征及其与NF-kB激活的关系；考查SM22α及其磷酸化修饰对IKKβ-IkBα-NF-kB级联活化的影响、相互作用和靶分子；SM22α表达与炎症诱导的IkBα磷酸化降解的关系。以SIRT1-EZH2轴为靶标，确定炎症刺激下SM22α表达下调与组蛋白乙酰化和甲基化的动态关系及其上游信号途径；阐明SIRT1-EZH2轴介导SM22α基因表观遗传学沉默的机制和分子途径；揭示SM22α与细胞炎症应答相互作用的机制及在血管炎症发生中的意义；寻求基于SM22α信号调节功能的抗血管炎症新途径

We first performed transcriptome profiling of aortic tissues in Sm22-/- mice and wild type (WT) mice littermates (Sm22+/+), and found that loss of SM22α was accompanied by increased expression of pro-inflammatory genes and increased tendency to vascular diseases. The upstream regulator analysis by IPA showed that NF-κB (RelA) was the major transcription regulator that was activated in Sm22-/- mice. However, the interaction of SM22α with cell inflammatory response is unclear. The goals of the project were to investigate the expression and dynamic modification of SM22α in vascular smooth muscle cells (VSMC) upon inflammatory stimulation, and its relationship with NF-ҝB activation, to examine the effects of SM22α on IKKβ-IҝBα-NF-ҝB cascade activation, IҝBα phosphorylation and degradation, as well as the target. We are going to determine the association of SM22α downregulation with histone modification and the upstream signaling pathway, to elucidate the role and mechanism of SIRT1 in epigenetic silencing of SM22α expression via suppression of EZH2-mediated H3K27 histone methylation in the gene promoter region. Our findings will reveal a critical role for SM22α in controlling NF-κB activity and vascular inflammation, and suggest that SM22α may serve as a new target to design therapeutic drug and to prevent further organ damage in vascular inflammatory diseases.

我们通过转录组测序发现，在SM22α（转凝蛋白）敲除小鼠的血管炎症相关基因表达明显上调；这些高表达的基因均受控于NF-kB；SM22α敲除小鼠显示出增加的血管炎症。然而， SM22α与细胞炎症应答之间的相互关系尚未阐明。本项目从炎症信号转导入手，分别探寻炎症刺激下，血管平滑肌细胞SM22α表达水平和动态修饰变化特征及其与NF-kB激活的关系；取得如下研究成果：1）发现CK2-SIRT1-SM22α是一个新的抑制血管炎症分子环路，SM22α和SIRT1在抑制血管炎性应答中具有协同作用。SM22α可作为支架蛋白募集CK2和SIRT1，促进二者的相互作用和SIRT1的磷酸化活化。EZH2介导启动子区组蛋白H3K27的甲基化导致SM22基因转录抑制，SIRT1激活可解除EZH2的甲基化活性，上调SM22基因转录活性。2）SM22α缺失诱发腹主动脉瘤（AAA）形成。SM22α KO小鼠的AAA发生率明显高于WT小鼠，AAA组织中，炎性因子表达明显升高；血管壁中膜和外膜处有大量巨噬细胞浸润，粘附分子VCAM-1表达水平明显高于野生型。3）证实平滑肌非编码环 RNA circ-Sirt1通过两种不同的机制抑制NF-κB激活和血管炎症应答。4）初步证实缺失KCNQ4可抑制血管炎症应答和腹主动脉瘤形成。