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Gene therapy for atherosclerosis by inhibition of nuclear transcriptional factor

通过抑制核转录因子进行动脉粥样硬化的基因治疗

基本信息

批准号：
07457174
负责人：
KITAJIMA Isao
金额：
$ 1.02万
依托单位：
Kagoshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

The proliferation of vascular smooth muscle cells (VSMCs) is the most crucial cause of artherosclerosis. High expression of thrombin receptor (TR) in athrosclerotic lesions indicates a possible role for athrogenesis. In the present study, we demonstrated that post TR signaling were mediated by several protein kinases resposible for nuclear transcriptional factor, NF-kappaB activation and thrombin-inducible genes had the kappaB sequence in the regulatory elements. Thrombin stimulation in VSMCs resulted in a biphasic activation of NF-kappaB,the early phase of which indicated nuclear translocation of NF-kappaB and the late phase of which required new synthesis, resulting in proliferation of VSMC.Furthermore, treatment of VSMCs with antisense p65 oligodeoxynucleotides (ODNs) of NF-kappaB inhibited thrombin-stimulated growth of VSMCs in vitro. Next, we examined whether the antisense ODNs for NF-kappaB could affect in vivo. We used the mouse model of lipopolysaccharide (LPS) induced septic shock, because it is associated with activation of NF-kappaB.We showed that all mice treated with LPS ultimately died within 48 hrs, while mice pretreated with the antisense NF-kappaB ODNs had a significantly better outcome and the survival rate was 60%. This suggested the greatest advantage antisense NF-kappaB provides an important new therapeutic approach for the treatment with athrerosclerosis and LPS-induced septic shock in vitro and in vivo. Moreover, we have studied a novel biomaterial vessle using aramid-silicon to intruduce the antisense ODNs.

血管平滑肌细胞（VSMC）的增殖是动脉粥样硬化的最重要原因。凝血酶受体（TR）在关节炎病变中的高表达表明其在关节炎发生中可能起作用。在本研究中，我们证明TR后信号传导是由几种负责核转录因子、NF-kappaB激活和凝血酶诱导基因的蛋白激酶介导的，这些基因在调节元件中具有kappaB序列。凝血酶刺激VSMCs可导致NF-κ B的双相激活，早期NF-κ B核转位，晚期NF-κ B需要新的合成，导致VSMCs增殖，NF-κ B反义p65寡核苷酸（ODNs）处理VSMCs可抑制凝血酶刺激的VSMCs增殖。接下来，我们检查了NF-κ B的反义ODNs是否可以在体内影响。我们使用脂多糖（LPS）诱导的脓毒性休克小鼠模型，因为它与NF-κ B的活化有关。我们发现，所有用LPS处理的小鼠最终在48小时内死亡，而用反义NF-κ B ODNs预处理的小鼠具有显著更好的结果，存活率为60%。这表明，最大的优势反义NF-κ B提供了一个重要的新的治疗方法与动脉粥样硬化和LPS诱导的感染性休克在体外和体内的治疗。此外，我们还研究了一种新型的以芳香族聚酰胺-硅为载体的生物载体，用于反义寡核苷酸的导入。