Endoglin蛋白在高脂介导冠状动脉粥样硬化中的作用及信号机制研究

Pathogenesis of hypercholesterolemia induced coronary atherosclerosis (CAS) is closely related to immunodysfunction, in which monocyte-macrophage system plays important role. In our previous study, we analyzed monocyte expression pattern from familial hypercholesterolemia (FH) patients, and revealed that Endoglin expressed significantly lower in patient with a suppressed SMAD signaling pathway, but on the contrary, IFN /TNF pathways and down-stream cytokines were shown activated. This results were partially verified in hypercholesterolemia CAS animal model. We therefore infer that erroneous Endoglin expression promotes dysfunction of TGF-ßRI/II-SMAD during pathogenesis of hypercholesterolemia induced CAS. This proposal aims to study Endoglin and immune activation and suppression by monoclonal antibody conjugated CPP-shRNA /Overexpression system to specifically knock down or overexpress Endoglin protein in mono-macrophage cell line in rat body. Further analysis of T, B and foam cells as well as local and systemic immune response will be carried out to find out connection between immune activation or immune suppression molecules and effect of Endoglin. This study facilitates our understanding of how Endoglin act as an immune suppressive molecule during pathogenesis of hypercholesterolemia induced atherosclerosis and its molecular mechanism.

高脂引起单核-巨噬细胞系统免疫反应对冠状动脉粥样硬化（CAS）发病的调节机制是目前学界研究热点。本课题组通过分析家族性高脂血症(FH)患者单核细胞样本表达谱芯片发现Endoglin蛋白表达量显著下降，下游抑炎信号通路SMAD家族也不同程度受到抑制，而促炎通路IFN/TNF等被激活，并在CAS动物模型中部分得到验证。因此我们推测Endoglin蛋白在高脂干预下对TGF-ßRI/II-SMAD通路介导的免疫炎症反应具有重要的意义。本课题组将以Endoglin蛋白免疫激活和抑制为切入点出发，利用单克隆抗体-CPP-shRNA/过表达系统，对动物模型体内单核-巨噬细胞特异性Endoglin沉默和过表达，T、B、泡沫细胞等免疫细胞在粥样斑块局部分布情况和数量变化及系统性免疫因子分泌量变化的测定，深入探究Endoglin对于高脂干预冠状动脉粥样硬化的调控作用及可能的分子机制。