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）的增殖是造成皮毛性的最关键原因。凝血酶硬化病变中凝血酶受体（TR）的高表达表明促进性的作用。在本研究中，我们证明了TR信号传导是由几种蛋白激酶在核转录因子，NF-kappab激活和凝血酶诱导的基因中介导的，在调节元素中具有KAPPAB序列。 VSMC中的凝血酶刺激导致NF-kappab的双相激活，其早期阶段表明NF-kappab的核易位需要新的合成，从而导致VSMC.Furthermore的增殖，对VSMC的vsmc对NFSMC进行了p65 opligyoxynucligyoxynucsynucsynucididides（ODN）的处理。凝血酶在体外刺激了VSMC的生长。接下来，我们检查了NF-kappab的反义ODN是否可能影响体内。我们使用了脂多糖（LPS）诱导的败血性休克的小鼠模型，因为它与NF-kappab的激活有关。我们表明，所有用LPS治疗的小鼠最终死亡的所有小鼠在48小时内死亡，而用反义NF-kappab ODN进行预处理的小鼠的结果和生存率更高，生存率为60％。这表明，最大的优势反义NF-kappab为通过促进性和LPS引起的体外和体内的败血性休克提供了一种重要的新治疗方法。此外，我们已经使用芳香硅硅侵入了反义ODN的新生物材料容器。