NOS-JNK-Cdk5 linkage in neurodegeneration of amyotrophic lateral sclerosis.

肌萎缩性脊髓侧索硬化症神经变性中的 NOS-JNK-Cdk5 连锁。

• 批准号: 15590917
• 负责人: ITO Hidefumi
• 金额: $ 1.86万
• 依托单位: Kansai Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590917/
• 关键词: ALS; transgenic mouse; ER stress; GRP78; nucleocytoplasmic transport; importin; IBM-BMT; edaravone; SOD1; iNOS; SREBP-2; β-catenin; amyotrophic lateral sclerosis; MAP kinase; JNK pathway; karyopherin

1.We found the immunohistochemical colocalization of endoplasmic reticulum (ER) chaperone, glucose regulated protein 78 (GRP78), with the mutant SOD1 within Lewy body-like hyaline inclusions (LBHIs) in the lumbar spinal cord from G93A transgenic mice. The immunoreactivity was distributed diffusely within LBHIs, and was positive even in those of their earliest emergence, suggesting that GRP78 would be related to LBHI formation.2.We found the reduced immunoreactivity of nucleocytoplasmic transport-related proteins such as importin beta, importin alpha, histone H1, and beta-catenin, in the nucleus of the remaining anterior horn cells of the transgenic mice. Moreover, we demonstrated the abnormal accumulations of these proteins in the cytoplasm of these cells and in LBHIs. Our results suggest that dysfunction of the nucleocytoplasmic transport would be involved in the pathomechanisms of the transgenic mice.3.We found the statistically significant suppressive effect of edaravone, one of the free radical scavengers, on the clinical disease progression of G93A SOD1 transgenic mice. Pathologically, the number of the remaining anterior horn cells was found to be proportional to the daily dose of edaravone. Furthermore, the 3-nitrotyrosine/tyrosine ratio, which reflects the extent of oxidative stress, in the spinal cord homogenates was lower in the edaravone-administered transgenic mice than those of controls.4.We found that intra bone marrow-bone marrow transplantation (IBM-BMT) from wild type mice to G93A transgenic mice ameliorated their decline of motor function. Pathological investigation of the recipients revealed that transplanted cells migrated into the spinal cords and a subset of these cells expressed Iba-1, a marker of microglia.

1.我们在G93A转基因小鼠的腰髓中发现了内质网伴侣蛋白葡萄糖调节蛋白78(GRP78)与突变型SOD_1在LBHIs内的免疫组织化学共存。GRP78可能与LBHI的形成有关。2.我们发现在转基因小鼠剩余的前角细胞中，核质转运相关蛋白如Importinβ、Importinα、组蛋白H1和β-catenin的免疫反应性降低。此外，我们还证明了这些蛋白质在这些细胞的细胞质和LBHIs中的异常积累。我们的结果提示核质转运功能障碍可能参与了转基因小鼠的发病机制。3.我们发现自由基清除剂之一依达拉奉对G93A SOD1转基因小鼠的临床疾病进展有显著的抑制作用。病理上，残留的前角细胞的数量与依达拉奉的每日剂量成正比。此外，服用依达拉奉的转基因小鼠脊髓匀浆中反映氧化应激程度的3-硝基酪氨酸/酪氨酸比值低于对照组。4.我们发现，从野生型小鼠到G93A转基因小鼠的骨髓内移植(IBM-BMT)改善了它们的运动功能下降。对受者的病理检查显示，移植的细胞迁移到脊髓中，其中一部分细胞表达小胶质细胞的标志Iba-1。

项目成果

MAP kinase phosphatase-1 is induced in abnormal fibers in inclusion body myositis.

MAP 激酶磷酸酶-1 在包涵体肌炎的异常纤维中被诱导。

• 发表时间: 2003
• 期刊: Neurology 61
• 作者: Zang J;et al.;Nakano S et al.
• 通讯作者: Nakano S et al.

In situ identification of hepatitis C virus RNA in muscle

• DOI: 10.1212/01.wnl.0000154605.02737.fe
• 发表时间: 2005-03-22
• 期刊: NEUROLOGY
• 影响因子: 9.9
• 作者: Ito, H;Ito, H;Kusaka, H
• 通讯作者: Kusaka, H

Nucleolar characteristics of reducing bodies in reducing body myopathy

• DOI: 10.1007/s00401-003-0806-y
• 发表时间: 2004-01
• 期刊: Acta Neuropathologica
• 影响因子: 12.7
• 作者: A. Shinde;S. Nakano;H. Kusaka;Yoshifumi Nakaya;H. Sawada;N. Kohara;H. Shibasaki

A unique muscle electronmicroscopic observation in a patient with distal myopathy, respiratory failure, and sick sinus syndrome

对患有远端肌病、呼吸衰竭和病态窦房结综合征的患者进行独特的肌肉电子显微镜观察

• 发表时间: 2004
• 期刊: Neuropathology 24
• 作者: Nakano S;et al.
• 通讯作者: et al.

Macrophage colony-stimulating factor (M-CSF), as well as granulocyte colony-stimulating factor (G-CSF), accelerates neovascularization

• DOI: 10.1634/stemcells.2004-0190
• 发表时间: 2005-03-01
• 期刊: STEM CELLS
• 影响因子: 5.2
• 作者: Minamino, K;Adachi, Y;Ikehara, S
• 通讯作者: Ikehara, S