同型半胱氨酸经TLR4蛋白赖氨酸乙酰化修饰差异性调控下游信号通路介导免疫炎症反应的分子机制

The inflammatory immune response is an important mechanism in homocysteine (Hcy) induced Atherosclerosis (As), and throughout the entire process of As. Toll-like receptor 4 (TLR4) is an important target which regulates immune and inflammatory response. In our previous studies also observed that TLR4 is involved in the regulation of Hcy induced by As, but the lack of high specificity and the mechanism is still unclear. Therefore, to deeply explore the regulatory mechanism of TLR4 has become a hot spot of research. Different sites of protein lysine residues acetylation modification can precise regulat the intracellular signaling pathways, therefore, our hypothesis is that Hcy via TLR4 protein lysine acetylation modification difference regulating the downstream signaling pathways mediated immune inflammation,which promotes the formation of As. This subject is based on the previous successful replication of the Hcy As model, using molecular biology technique, from an overall and cell levels to observe Hcy induced CBP out/in nuclear regulating the change of acetylation binding domain and translocation. To explore the mechanism of TLR4 and its different sites lysine residues acetylation modification in the role of Hcy induced inflammatory immune response. To reveal the mechanism of TLR4 difference regulating adaptor protein MyD88 and TRAM/TRIF mediated downstream signaling pathway and identify the key targets,which to provide a new idea of targeted therapy for As.

免疫炎症反应是同型半胱氨酸(Hcy)致动脉粥样硬化(As)的重要机制，且贯穿于As形成的全过程，而Toll样受体4(TLR4)是调节免疫炎症的重要靶标，课题组前期也观察到TLR4参与了Hcy致As的调控，但缺乏高特异性且机制仍未清楚，因此深入探讨TLR4的调控机制成为研究的热点。蛋白质赖氨酸残基不同位点乙酰化修饰可对细胞内的信号通路进行精确调控，故我们的假说是：Hcy经TLR4蛋白赖氨酸乙酰化修饰差异性调控下游信号通路介导了免疫炎症反应促进了As的形成。本课题基于前期成功复制Hcy As模型的基础上，采用分子生物学等技术，从整体和细胞水平观察Hcy诱导CBP出/入核调控乙酰化中的结合域和转位变化，探讨TLR4及其赖氨酸残基不同位点乙酰化修饰在Hcy致免疫炎症反应中的作用机制，揭示TLR4差异性调节接头蛋白MyD88和TRAM等介导下游信号通路的机理，确定关键靶点，为As靶向治疗提供新思路。

背景：同型半胱氨酸(Hcy)是动脉粥样硬化(As)的致病的独立危险因素，免疫炎症反应是Hcy致As的重要机制，且贯穿于As形成的全过程，而Toll样受体4(TLR4)是调节免疫炎症的重要靶标，课题组前期也观察到TLR4参与了Hcy致As的调控，但缺乏高特异性且机制仍未清楚。.内容：本课题基于前期成功复制高同型半胱氨酸血症As模型的基础上，采用分子生物学等技术，从整体和细胞水平观察Hcy诱导CBP调控TLR4乙酰化变化，探讨TLR4及其乙酰化修饰在Hcy致免疫炎症反应中的作用机制，确定关键靶点，为As靶向治疗提供新思路。.结果：分别在动物水平和细胞水平检测到Hcy组TLR4的表达增加，炎症因子的分泌增加，而将TLR4干扰后能够降低Hcy引起的炎症因子的分泌增加，并且Hcy可以改变TLR4乙酰化水平，将EGFP-N1-CBP 转染细胞后，TLR4乙酰化水平明显增加而pGenesil-CBP 转染细胞后，TLR4乙酰化水平明显降低。.该项目共发表SCI论文7篇，中文期刊2篇，专著2部，专利1个。.意义：该课题的实施有利于进一步研究动脉粥样硬化发生发展的分子机制，寻找致病环节，确定关键靶点，为动脉粥样硬化这一疾病的防治工作提供更多研究资料。

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