LOX-1 靶向的化学基因沉默药物洗脱球囊在抗动脉粥样硬化中的作用

Atherosclerosis (AS) is a serious threat to human health. The focal nature of AS-targeted lesion makes it a highly attractive target for locally gene silencing. The interaction between lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and its receptors plays a crucial role in the development of AS. Utilizing molecular technology to silence the expression of LOX-1 might have anti-atherosclerosis effect.Drug-eluting balloon(DEB) combines the advantages of   medication and interventional therapy, which makes it a optimal drug-carrier for locally gene sillencing therapy.Pyrrole-imidazole polyamide (PIP) is a novel gene silencer that can be readily designed and synthesized to target any gene. Compared with traditional gene-silencing agents, PIP can enter into the nuclei of target cells without any particular delivery system and is resistant to nucleases. Moreover, PIP has a high efficiency of cellular uptake and bioavailability, making it pharmacokinetically suitable for its application in DEB. The present study aimed to assess the effect of PIP targeting LOX-1 coated DEB on the prevention of atherosclerosis. To design PIP targeting rat LOX-1 gene promoter and evaluated its effecting on silencing LOX-1 gene. To assess the effect of PIP targeting LOX-1 on inhibiting the transformation of macrophages into foam cell in vitro. To establish the model of AS in rats in vivo, and to evaluate the effect of PIP coated DEB on the prevention of AS and investigate the possible mechanism.

动脉粥样硬化性疾病(AS)严重危害人类健康。AS靶病变局部化的特征使得局部的基因沉默治疗成为可能。凝集素样氧化型低密度脂蛋白受体-1(LOX-1)在AS的发生发展中起着重要作用，特异性地沉默LOX-基因有望取得抗AS的效果。融合了药物治疗与介入技术各自优点的药物洗脱球囊（DEB）可能是局部特异性基因沉默药物的最佳载体。吡咯-咪唑聚酰胺(PIP)是一种能使特定基因沉默的化合物，其具有进入细胞核不借助载体、对核酸酶耐受、结构稳定、细胞摄取率及生物利用度高等优点，非常适合应用于DEB上。本研究旨在探讨针对LOX-1的PIP-DEB在抗AS中的作用。我们拟构建针对大鼠LOX-1基因的PIP，观察其对LOX-1基因的特异性沉默作用，然后在体外探讨PIP对大鼠巨噬细胞向泡沫细胞转化的抑制作用；在体内建立大鼠AS的动物模型，观察针对LOX-1的PIP-DEB的抗AS作用并探讨相应机制。

动脉粥样硬化性疾病(AS)严重危害人类健康。AS靶病变局部化的特征使得局部的基因沉默治疗成为可能。凝集素样氧化型低密度脂蛋白受体-1(LOX-1)在AS的发生发展中起着重要作用，特异性地沉默LOX-基因有望取得抗AS的效果。融合了药物治疗与介入技术各自优点的药物洗脱球囊（DEB）可能是局部特异性基因沉默药物的最佳载体。吡咯-咪唑聚酰胺(PIP)是一种能使特定基因沉默的化合物，其具有进入细胞核不借助载体、对核酸酶耐受、结构稳定、细胞摄取率及生物利用度高等优点，非常适合应用于DEB上。本研究旨在探讨针对LOX-1的PIP-DEB在抗AS中的作用。我们拟构建针对大鼠LOX-1基因的PIP，观察其对LOX-1基因的特异性沉默作用，然后在体外探讨PIP对大鼠巨噬细胞向泡沫细胞转化的抑制作用；在体内建立大鼠AS的动物模型，观察针对LOX-1的PIP-DEB的抗AS作用并探讨相应机制。