lncRNA O11RIK在白藜芦醇抗动脉粥样硬化中的作用及机理研究

Atherosclerosis is a chronic inflammatory disease and has become a core scientific problem of cardiovascular and cerebrovascular diseases. Resveratrol is a hotspot project in the field of atherosclerosis (AS), nevertheless the concrete molecular mechanism is unknown. Researchers reveal that long noncoding RNAs (lncRNAs) plays critical role in development of the AS. The project preliminary result showed that resveratrol could reduce macrophage infiltration and the plaque area on AS. The Gene Chip result manifested that resveratrol dominantly upregulated the level of lncRNA O11RIK, further studies were applied to figure out five crucial targets, which were identified to be closely related to inflammation and immune response process. Therefore, the applicant predicated that O11RIK is a key target during protecting against AS. According to the predication, O11RIK was first chosen as therapeutic target. In order to make the project without any obstacles, lentivirus knockdown and overexpression technologies were applied, and medical imaging and molecular biology method were used. The various facets including molecular, cellular and animal levels were studied. The complicated resveratrol-O11RIK-target genes regulatory networks were revealed in new mechanism and targets. It will provide new ideas and measurements for AS prevention and treatment.

动脉粥样硬化是全球重大慢性炎症疾病，已成为心脑血管疾病共性核心科学问题。白藜芦醇是当今动脉粥样硬化（AS）领域研究的热点之一，但确切作用机制尚不清楚。研究证实长链非编码RNAs（lncRNAs）对AS的发生发展至关重要。本项目初步结果显示白藜芦醇能够降低巨噬细胞浸润、缩小AS斑块面积。芯片结果表明白藜芦醇明显上调小鼠AS斑块lncRNA O11RIK基因的表达，进一步通过UCSC网络预测结合基因芯片筛选出5个关键的O11RIK的靶基因，显示其具有调控涉及炎症和免疫反应等过程。因此，申请人推测O11RIK是白藜芦醇抗AS的关键靶点。为证实这一假说，本项目组首次以O11RIK为靶点，应用慢病毒基因过表达和沉默技术，采用医学影像学和分子生物学相结合的方法，从分子、细胞、动物多层次系统阐明白藜芦醇—O11RIK—靶基因调控网络，揭示白藜芦醇防治AS的新机制、新靶点，为AS的防治提供新思路和新措施。

动脉粥样硬化（AS）是全球重大慢性炎症疾病，已成为心脑血管疾病共性核心科学问题。白藜芦醇（Rev）是当今动脉粥样硬化（AS）领域研究的热点之一，但确切作用机制尚不清楚。本课题采用HE染色，油红O染色，免疫组织化学技术以及PCR和Western blot技术多角度从活体和细胞层面多层次的炎症Rev具有较好的抗AS作用，并发现新的基因AI662270。发现Rev能够调控AI662270进而发挥抗AS作用。本课题创新点在于首次发现或揭示了：1) Rev能够降低高脂饮食引起斑块增大；降低斑块内泡沫细胞的形成；减少斑块总胆固醇含量，升高HDL胆固醇水平；此外，长期给予Rev不影响高脂饮食引起的小鼠体重增加；2) Rev通过调控腹部肌肉及肠道的脂质和氨基酸代谢发挥抗AS作用；3）Rev能够降低长链非编码RNA AI662270发挥抗AS作用。4）AI662270过表达促进ApoE-/-形成动脉斑块，增加总胆固醇水平，降低HDL水平，不影响甘油三酯表达； 5）AI662270过表达促进巨噬细胞积聚，但不影响斑块内胶原含量；6)增加AI662270能够促进斑块内脂质积聚，从而促进AS的发生发展；7）Rev未来可开发协助抗AS的新药物；AI662270未来可成为AS损伤的防治新靶点。