SIRT1基因与miR-UL112-1在脑动脉粥样硬化斑块内血管新生中的作用和机理研究

Atherosclerosis plays a key role of the pathological angiogenesis in development process, which often leads to atherosclerosis plaque formation, vascular stenosis, vulnerable plaque rupture, and increased the risk of the acute cerebrovascular events. However, the pathogenesis of angiogenesis remains unclear now.It has been studied relatively mature for angiogenesis in the plaque outside, but the study of angiogenesis within the plaque is not intensive enough. Our previous studies outcome of the former National Natural Science Foundation and abroad showed that cytomegalovirus infection of vascular cells in vitro can promote angiogenesis occurs, SIRT1 gene and miR-UL112-1 inhibit angiogenesis after cytomegalovirus infection. miR-UL112-1 has been found a potential target for regulation of SIRT1 gene activity now.Therefore, we hypothesized that miR-UL112-1 may be inhibit atherosclerotic plaque angiogenesis occurs through some kind of signaling pathways of SIRT1 gene，but the results of relevant in vivo are not clear.We will study the roles of SIRT1 gene and miR-UL112-1 in angiogenesis of cerebrovascular atherosclerotic plaque by miRNAs technology, molecular imaging advanced technologies , transgenic animal models and explore the issue of pathogenesis of the SIRT1 gene and miR-UL112-1 in the pathological angiogenesis . Our study is of great significance on illustration the mechanism of pathological angiogenesis. The study findings will provide new ideas to seek new molecular markers for early diagnosis and new therapeutic targets of the cerebrovascular diseases.

动脉粥样硬化斑块内血管新生常导致斑块的形成、血管狭窄、易损斑块的破裂,危害极大。迄今对斑块外血管新生的研究已相对成熟，而对斑块内血管新生的研究不够深入。巨细胞病毒感染体外培养血管细胞能够促进血管新生。我们前一项国家自然基金的成果及在国外的工作发现：SIRT1基因及 miR-UL112-1能够抑制病毒感染后的血管新生，而且miR-UL112-1具有调控SIRT1基因活性的潜在靶点。据此推测，miR-UL112-1可能通过调控SIRT1基因抑制脑动脉粥样硬化斑块内血管新生，但动物体内实验结果尚不清楚。本课题拟采用miRNAs技术、分子影像等先进技术，利用转基因动物，探讨巨细胞病毒感染后，SIRT1基因及miR-UL112-1在脑动脉粥样硬化斑块内血管新生中的作用及机理。这对阐明病理性血管新生的发病机制，寻求早期诊断分子标记物和有效的治疗靶点具有重要意义。

炎性反应是动脉粥样硬化斑块不稳定性的原因之一，急性感染被证实可诱导急性炎性反应。巨细胞病毒感染诱导的急性炎性反应比病毒感染本身更易诱导斑块破裂，但目前作用机制目前上不清楚，本课题正就此进行相应研究。本课题探讨斑块新生血管与斑块破裂的相关性，SIRT1在巨细胞病毒诱导的血管新生中的作用及调控靶点，进一步研究HCMV-miR-UL112-1与SIRT1调控关系。我们研究结果发现 SIRT1、FOXO3和eNOS参与调控HCMV感染相关性血管新生，其中eNOS是SIRT的下游作用靶点，SIRT具有抑制巨细胞病毒感染相关血管新生的作用，其次miR-UL112-1具有直接结合SIRT1 3`UTR端的作用，抑制SIRT1蛋白表达，促进巨细胞病毒诱导的血管新生，此外，我们还发现miR-199a-5p和miR-217表达水平在巨细胞病毒感染的血管内皮细胞内高表达，都可结合到SIRT1 3`UTR，抑制SIRT1表达，最终抑制血管内皮细胞迁移和成管功能。本课题进一步探讨了CMV感染诱导的血管新生的机制，提出SIRT1具有明显抑制CMV感染相关血管新生的作用和调控SIRT1表达的靶点，为研究诊断和开发可能控制易损斑块破裂的治疗靶点提供了一定研究背景，具有明确的临床应用的基础和前景。

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