基于多组学数据整合的血流剪切力对内皮细胞功能调控的系统生物学研究

Atherosclerosis is prone to develop in the arterial branches and curvatures, the molecular mechanism of which had not been clarified. The research on hemodynamics revealed that sustained laminar flow upregulates expressions of endothelial cells (EC) genes that are protective against atherosclerosis, whereas disturbed flow upregulates the EC genes promote EC dysfunction. We found that eicosanoids responded to the hemodynamic forces and regulated the EC function. This suggested the complex regulation network made up by genes and small molecular metabolites. LncRNA could regulate gene expression, but the regulation networks composed by genes, lncRNAs and metabolites under different hemodynamic forces were not clear. The objective of this project is to demonstrate the network by multi-omics strategy based on RNA-seq and metabolomics technique. The critical targets, targets combinations and pathways would be mined from the network via systems biology analysis, and their regulations on EC function and corresponding potential mechanisms would be studied in HUVECs. This study could contribute to our understanding on the mechanism of different hemodynamic forces on the activation of EC and the development of atherosclerosis.

动脉粥样硬化常见于发生湍流的动脉血管分叉或弯曲处，其分子机制尚未阐明。血流动力学研究揭示，层流具有内皮保护作用，而湍流造成内皮细胞功能障碍，血流方式造成基因表达的差异。我们前期工作发现，类二十烷酸代谢产物能响应血流剪切力的刺激，并调控内皮细胞的功能，这暗示类二十烷酸和基因之间存在复杂的调控网络。LncRNA能够调控基因的表达，但在血流剪切力刺激下lncRNA与基因、代谢产物之间的调控关系尚不清楚。本课题旨在通过基于RNA-seq和代谢组学的多组学策略，研究不同血流剪切力作用下由基因、lncRNA和代谢产物组成的调控网络，分析上述网络中的关键靶点、靶点组合或通路；通过多时间点定量信息推断变量之间的关系，发现各变量对血管内皮细胞的调控模式。最后在细胞模型中验证、并研究关键靶点、靶点组合和通路对内皮细胞功能的调控机制，以期阐明血流动力学改变在内皮细胞激活和动脉粥样硬化发生中的作用。

动脉粥样硬化常见于发生湍流的动脉血管分叉或弯曲处，但其分子机制尚未阐明。血流动力学研究揭示，层流具有内皮保护作用，而湍流造成内皮细胞功能障碍，血流方式造成基因表达调控的差异。本课题旨在通过基于RNA-seq和代谢组学的多组学策略，研究不同血流剪切力作用下由基因、lncRNA和代谢产物组成的调控网络。通过RNA-seq和聚类分析，我们发现了不同血流模式在不同时间点上对基因和lncRNA的调控模式上的不同；通过类二十烷酸靶向代谢组学我们发现了不同血流刺激对小分子活性脂质代谢产物的差异性调控；通过脂质组学全面了解了不同血流刺激的甘油磷脂、鞘脂和中性脂类等主要脂质成分的差异性调控；通过相关性网络分析，获得了基因与代谢产物之间的关系，获得了层流与湍流调控的不同模块。这些研究对阐明血流动力学改变在内皮细胞激活和动脉粥样硬化发生中的作用有重要意义。