柯里拉京对外周动脉疾病发病过程中TLR-4信号通路的干预作用机制研究

Peripheral arterial disease (PAD) is leaded by atherosclerosis, which has limited therapeutic effect nowadays. Recent studies have found that, a large release of pro-inflammatory cytokines and the formation and stability of arteriosclerosis plaque in the pathogenesis of PAD are related to TLR-4 signaling pathway closely. Our previous studies have shown: corilagin inhibits the expression of TLR-4 and its relative molecules. Therefore, we hypothesized: whether corilagin could control PAD through inhibiting TLR4 signaling pathway. This study intends to clarify corilagin intervention mechanism for TLR4 signaling pathway by corilagin intervening in PAD cell model and animal experiments. The experiments with RAW264.7, primary rat peritoneal macrophages and human peripheral blood mononuclear cells, using TLR-4-specific endogenous stimulator (ox-LDL) and LPS to stimulate, following by the corilagin intervention, are aimed at confirming the corilagin intervention mechanism for TLR-4 signaling pathway, by small RNA molecules interference, lentiviral vector technology and other methods; and there will be a further validation in vivo. Through this research, a reliable theoretical basis will be provided for more effective clinical control of PAD.

外周动脉疾病（PAD）由动脉粥样硬化导致，目前治疗效果有限。近期研究发现，PAD发病过程中大量促炎细胞因子释放导致动脉硬化斑块的形成与破裂，该过程与TLR-4相关信号通路有密切关系。我们的前期研究显示：柯里拉京对TLR-4及其相关分子有抑制作用。因此，我们提出假设：柯里拉京是否能通过抑制TLR-4信号通路起到控制动脉硬化斑块进展的作用？本课题拟通过细胞和动物两个层面进行展开。实验分别以RAW264.7，大鼠腹腔原代巨噬细胞及人外周血单核细胞为模型，采用TLR-4特异性刺激物ox-LDL和LPS刺激，利用小分子RNA干扰技术，慢病毒载体技术等方法下调或上调TLR-4以及其相关信号分子，同时给予柯里拉京干预，在细胞层面上证实柯拉京对TLR-4信号通路的干预作用机制；并进一步在动物体内验证。通过此项研究，为寻找临床更有效控制PAD的方法提供理论基础和实验依据。

动脉硬化闭塞症（ASO）是最常见的外周动脉疾病（PAD）之一，由动脉粥样硬化导致，目前治疗效果有限。近期研究发现，ASO发病过程中大量促炎细胞因子释放导致动脉硬化斑块的形成与破裂，该过程与TLR-4相关信号通路有密切关系。本课题拟通过细胞和动物两个层面进行展开。实验分别以Ana-1，小鼠腹腔原代巨噬细胞为细胞模型，采用TLR-4特异性内源刺激物（ox-LDL）刺激，利用小分子RNA干扰技术，慢病毒载体技术等方法下调或上调TLR-4信号分子，同时给予柯里拉京干预，在细胞层面上证实柯拉京对TLR-4信号通路的干预作用机制；利用机械损伤内皮后高脂高胆固醇饮食喂养大鼠三个月建立大鼠模型，并进一步在该模型体内验证我们的猜想。通过此项研究，明确柯里拉京对动脉粥样硬化过程中TLR4信号通路的干预机制，为寻找临床更有效控制ASO的方法提供理论基础和实验依据。