动脉粥样硬化(AS)是心脑血管缺血性疾病的重要病理基础，现有抗AS治疗策略下晚期斑块的残存风险依然较大。lncRNAs在众多生理病理状态下发挥重要功能，不同AS阶段lncRNA分布是否具有特异性，并调控AS进展影响其治疗效果，目前尚不清楚。我们通过基因测序发现lncRNA在早期与晚期斑块中明显差异表达，其中在巨噬细胞及晚期AS斑块显著高表达的lncRNA Gm14636与冠心病患者斑块易损性显著相关。进一步结合生物信息预测与前期实验结果，我们合理推测Gm14636表达受到转录因子FoxO1调控，其作为ceRNA调控巨噬细胞功能进而促进AS进展与影响干预效果。本课题将利用OCT与MRI等影像模式并结合基因转染、ChIP及FISH等技术从细胞到整体水平阐明Gm14636对巨噬细胞功能与AS动态演变的作用并揭示其上下游调控机制。预期为阻断早期AS向晚期进展及晚期AS的治疗提供新靶点。

Atherosclerosis (AS) has been an important pathological foundation of ischemic cardiovascular and cerebrovascular diseases. Despite the current anti-atherosclerosis therapy, residual risk of late-stage atherosclerotic plaques remains high. lncRNA is considered to play an important regulatory role in various pathophysiological states. However, it is still unclear whether lncRNA has a specific distribution in different AS stages which regulates progression of AS and effects its intervention. We found that lncRNAs are significantly differently expressed in early and late stages atherosclerotic plaques by gene sequencing. Among them, high expressed lncRNA Gm14636 in macrophages and late-stage atherosclerotic plaques significantly influences plaque vulnerability in clinical patients. Thus, combined with biology information analysis and preliminary experimental results we hypothesized that Gm14636 is regulated by the upstream transcription factor FoxO1 and acts as a ceRNA to regulate macrophage function which affects the progression and intervention of AS plaque. Our present study will use OCT, MRI image modalities combined with gene silencing, ChIP and FISH techniques to elucidate the effects of Gm14636 on macrophage function and AS dynamic evolution and its upstream and downstream regulation mechanisms from cell to overall level. The results will moreover provide a new therapeutic target for blocking progression from early to late stage atherosclerotic plaques.