Study on Pathogenesis of prion disease (A role of cytokines in spongiform formation in affected brains)

朊病毒病发病机制研究（细胞因子在受影响大脑海绵状形成中的作用）

基本信息

批准号：
09671002
负责人：
TAMAI Yoichi
金额：
$ 2.05万
依托单位：
Kitasato University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

1. It has been suspected that cytokines such as TNFα and IL1α participate in various neuropathological processes including spongy degeneration in transmissible spongiform encephalopathy. To explore this hypothesis, we inoculated Creutzfeld-Jakob disease (CJD) agent into brains of TNFα gene-deficient mice, and examined the expression of mRNAs of TNFα, IL1α, and glial fibrillary acidic protein (GFAP) by RT-PCR. The brains were also histologically and immuohistochemically examined. Both TNFα (+/+) and (-/-) mice showed clinical symptomes on 140 days after the inoculation. Overexpression of GFAP-mRNA was observed in all inoculated mice. Vacuolation of the brain tissues was observed at various levels diffusely in cereberum and cerebellum of TNFα (+/+) and (-/-) mice, in association with astologliaosis. There were no differences in neuropathological findings between TNFα (+/+) and (-/-) mice. Accumulation of PrPSc was detected particularly in the areas where vacuolation is prominent. Based o … More n the results obtained, it was concluded that TNFα is not an essential requirement for pathogenesis of CJD.2. We found heightened expression of inducible nitric oxide synthase (iNOS)-mRNA in the brain of mice inoculated with CJD agent. To elucidate the de of iNOS in pathogenesis of CJD, CJD agent was inoculated into iNOS gene-deficient mice. Incubation periods, clinical symptomes, accumulation of PrPSc, and histopathological findings showing spongy degeneration in brain were not different between iNOS gene (+/+) and (-/-) mice. Like the findings observed in the experiment with TNFα gene-deficient mice, it was found that iNOS is not n essential requirement for pathogenesis of CJD.3. Neuronal cell loss and spongiform degeneration are prominent histopathological features in CJD. Previously, histopathological observation showed that neuronal loss in CJD occurs through a process of programmed cell loss, apoptosis. However, apoptotic processes have not been examined biochemically in CJD brain so far. In this study, we evidenced that apoptosis occurs in the brain of CJD mice, showing DM.X fragmentation. Less

1。人们怀疑细胞因子（例如TNFα和IL1α）参与了各种神经病理学过程，包括透射海绵状脑病的海绵变性。为了探索这一假设，我们接种了Creutzfeld-Jakob疾病（CJD）剂到TNFα基因缺陷小鼠的大脑中，并通过RT-PCR检查了TNFα，IL1α和神经胶质纤维化酸性蛋白（GFAP）的MRNA的表达。在组织学和免疫组织化学上，大脑也进行了检查。接种后140天，TNFα（+/+）和（ - / - ）小鼠均显示出临床症状。在所有接种小鼠中都观察到GFAP-MRNA的过表达。在TNFα（+/+）和（ - / - ）小鼠的小脑和小脑中，在各种水平上观察到了脑组织的空泡。 TNFα（+/+）和（ - / - ）小鼠之间的神经病理学发现没有差异。特别是在空泡突出的区域中检测到PRPSC的积累。基于o…更多的是获得的结果，得出的结论是TNFα不是CJD.2发病机理的必不可少的要求。我们发现与CJD剂接种的小鼠大脑中诱导型一氧化氮合酶（iNOS）-MRNA的表达升高。为了阐明CJD发病机理中iNOS的DE，将CJD剂接种到Inos基因缺陷型小鼠中。在iNOS基因（+/+）和（ - / - ）小鼠之间，培养期，PRPSC的积累和组织病理学发现没有差异。就像在TNFα基因缺陷型小鼠实验中观察到的发现一样，发现iNOS不是CJD.3发病机理的基本要求。神经元细胞丧失和赞助性变性是CJD中显着的组织病理学特征。以前，组织病理学观察结果表明，CJD的神经元丧失是通过程序性细胞丢失，凋亡过程发生的。但是，到目前为止，尚未在CJD大脑中对凋亡过程进行生化。在这项研究中，我们证明了凋亡发生在CJD小鼠的大脑中，显示了DM.X碎片。较少的