新型抗凋亡基因Tnfaip8介导的血管平滑肌细胞功能转变对动脉粥样硬化不同阶段的影响研究

Atherosclerosis (AS) is a complex disease process involving apoptosis and inflammation，the participation of vascular smooth muscle cell(VSMC) is critical in the development of AS. Tnfaip8 is a novel anti-apoptosis gene which plays an important role in cell malignant transformation, but the role of Tnfaip8 in VSMC and AS has not been reported yet. Our previous studies first showed Tnfaip8 overexpression dominantly affected the proliferation, apoptosis and migration of vascular smooth muscle cells(VSMC),indicating Tnfaip8 might affect the development of AS by regulating VSMC function.Further studies found that Tnfaip8 expression was significantly elevated in atherosclerotic coronary;Tnfaip8 overexpression enlarged the early lesion of atherosclerosis in ApoE-/- mice.Therefore,the aim of this project is to investigate the role and mechanism of Tnfaip8 in AS. First, we will construct Tnfaip8 overexpressing/silencing virus, then infect VSMC for in vitro study to examine the effect of Tnfaip8 on VSMC proliferation, apoptosis,migration and secretion and its mechanism; infect atherosclerotic mice at early or late stage for in vivo study to check the effect on the formation and stability.Our project will disclose the role and mechanism of Tnfaip8 in the formation and stability of atherosclerotic plaque and provide new target for AS treatment.

动脉粥样硬化（AS）是一种严重危害健康的涉及凋亡、炎症等复杂机制的疾病，血管平滑肌细胞(VSMC）的参与是其发生发展中的关键因素之一。Tnfaip8是新发现的一种抗凋亡基因，在多种细胞的癌性转化中发挥重要作用，但其在VSMC及AS中的作用尚未见报道。我们在前期研究中发现，Tnfaip8过表达可以明显影响VSMC的凋亡迁移等生物学特性，提示其可能通过调节VSMC的功能而影响AS的发生发展。进一步研究发现，Tnfaip8在发生AS的冠状动脉中表达显著升高，过表达Tnfaip8的AS早期模型小鼠斑块面积明显增大。因此，本课题拟通过构建Tnfaip8基因表达病毒和基因沉默病毒，体外感染原代培养的VSMC，检测对细胞增殖凋亡迁移及分泌功能等的影响及机制；体内感染AS早晚期模型小鼠，检测对斑块形成及稳定性等的影响。本课题将首次揭示Tnfaip8在AS发生发展中的作用及机制，并为疾病的防治筛选新的靶点。

动脉粥样硬化（AS）是严重危害人类健康的常见疾病，现已成为国际心血管基础与临床研究的热点。目前研究发现AS发病涉及凋亡、炎症等多种复杂机制，血管平滑肌细胞(VSMCs）的参与是其发生发展中的关键因素之一。本课题以新型抗凋亡基因Tnfaip8为靶点，研究其介导的VSMCs功能转变在AS进程中的作用。首先，我们制备了高滴度Tnfaip8基因表达和沉默病毒，以此感染小鼠VSMCs，发现Tnfaip8表达干预对细胞增殖迁移凋亡等能力有显著影响。进一步机制探讨发现，Tnfaip8对细胞功能的影响主要是通过MAPK通路发挥作用的。体内实验部分，我们以ApoE-/-小鼠高脂饲养建立了早期AS模型，发现Tnfaip8表达干预不影响小鼠的生理生化相关指标，而显著影响了AS斑块的大小、组成及炎性因子的分泌等。这与我们的预期基本一致。此外，我们还研究了Tnfaip8在小鼠腹主动脉瘤模型中的作用，发现Tnfaip8会促进小鼠腹主动脉VSMCs增生而促进腹主动脉瘤的进展。本项目的研究揭示了Tnfaip8可以活化MAPK通路而改变VSMCs功能，进而影响AS的进展，为AS的治疗提供了药物靶位。