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 TNFα 和 IL1α 等细胞因子参与各种神经病理过程，包括传染性海绵状脑病的海绵变性。为了探索这一假设，我们将克雅氏病 (CJD) 制剂接种到 TNFα 基因缺陷小鼠的大脑中。并通过检测 TNFα、IL1α 和胶质纤维酸性蛋白 (GFAP) 的 mRNA 表达RT-PCR。在接种后140天，对TNFα(+/+)和(-/-)小鼠的大脑进行了组织学和免疫组织化学检查，在所有接种的小鼠中都观察到了GFAP-mRNA的过度表达。在 TNFα (+/+) 和 (-/-) 小鼠的大脑和小脑中，在不同水平上观察到脑组织的变化。 TNFα (+/+) 和 (-/-) 小鼠的神经病理学结果没有发现差异，特别是在空泡形成明显的区域。结论是 TNFα 不是 CJD 发病机制的必需条件。2 我们发现接种小鼠脑中诱导型一氧化氮合酶 (iNOS)-mRNA 的呼吸表达。为了阐明 iNOS 在 CJD 发病机制中的作用，将 CJD 剂接种到 iNOS 基因缺陷小鼠体内，iNOS 基因之间的潜伏期、临床症状、PrPSc 积聚和组织病理学结果没有差异。 (+/+)和(-/-)小鼠与TNFα基因缺陷小鼠的实验中观察到的结果一样，发现iNOS是3. 神经元细胞丢失和海绵状变性是克雅氏病的重要组织病理学特征，之前的组织病理学观察表明，克雅氏病的神经元丢失是通过程序性细胞丢失、细胞凋亡过程发生的。迄今为止，尚未对克雅氏病大脑进行生化检查，在这项研究中，我们证明了克雅氏病小鼠大脑中发生了细胞凋亡，显示 DM.X 碎片较少。