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Establishment of new therapeutic strategies for neurogenetic disorders during childhood

建立儿童期神经遗传性疾病的新治疗策略

基本信息

批准号：
16390302
负责人：
OHNO Kousaku
金额：
$ 8.83万
依托单位：
Tottori University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

Gaucher disease (GD), caused by a defect of β-glucosidase (β-Glu), is the most common form of sphingolipidosis. We found that a carbohydrate mimic β-octyl-β-valienamine (NOV), an inhibitor of β-Glu, could increase the protein level and enzyme activity of F213I, N188S, G202R and N370S mutant forms of β-Glu in cultured cells. When expressed in COS cells, the mutant proteins as well as the wild-type protein were localized predominantly in the endoplasmic reticulum and were sensitive to Endo-H treatment. NOV did not alter this localization or Endo-H sensitivity, suggesting that it acted in the endoplasmic reticulum. Profiling of β-alkyl-β-valienamines with various lengths of the acyl chain showed that β-dodecyl-β-valienamine was as effective as NOV. These results suggest a potential therapeutic value of NOV and related compounds for GD with a broad range of β-Glu mutations.Niemann-Pick disease type C (NPC) is a lipid storage disorder caused by mutations in NPC1 (NPC2) genes. We found that human NPC fibroblasts secrete several cytokines and contain increased levels of STATs. These cells also contained increased levels of TLR4. In the NPC model mouse brain, glial cells expressed TLR4 and IL-6, whereas both glial and neuronal cells expressed STATs. Genetic deletion of TLR4 in NPC model mice reduced IL-6 secretion but failed to alter STAT levels or glial cell activation in the brain. In contrast, genetic deletion of IL-6 normalized STAT levels and suppressed glial cell activation. These findings indicate that constitutive cytokine secretion leads to activation of STATs and that this secretion is partly caused by an endosomal accumulation of TLR4. These results also suggest that similar signaling events may underlie glial cell activation in the NPC brain

戈谢病（GD）是由β-葡萄糖苷酶（β-Glu）缺陷引起的鞘脂病的最常见形式。我们发现糖模拟物β-辛基-β-维列胺（NOV）是β-Glu的抑制剂，它能提高培养细胞中F213 I、N188 S、G202 R和N370 S突变型β-Glu的蛋白水平和酶活性。当在COS细胞中表达时，突变蛋白以及野生型蛋白主要定位于内质网中，并且对Endo-H处理敏感。NOV没有改变这种定位或Endo-H敏感性，表明它在内质网中起作用。对不同酰基链长度的β-烷基-β-维列胺的分析表明，β-十二烷基-β-维列胺与NOV一样有效。这些结果表明，NOV及其相关化合物对β-Glu突变广泛的GD具有潜在的治疗价值。我们发现，人NPC成纤维细胞分泌几种细胞因子，并含有增加水平的STAT。这些细胞还含有增加水平的TLR 4。在NPC模型小鼠脑中，胶质细胞表达TLR 4和IL-6，而胶质细胞和神经元细胞均表达STAT。在NPC模型小鼠中，TLR 4的基因缺失减少了IL-6的分泌，但未能改变STAT水平或脑中胶质细胞的活化。相比之下，IL-6的基因缺失使STAT水平正常化并抑制神经胶质细胞活化。这些发现表明，组成型细胞因子分泌导致STAT的活化，并且这种分泌部分由TLR 4的内体积累引起。这些结果也表明，类似的信号事件可能是神经胶质细胞活化的基础在NPC脑

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Degeneration of cholecystokinin-immunoreactive afferents to the VPL thalamus in a mouse model of Niemann-Pick disease type C.

C 型尼曼-匹克病小鼠模型中 VPL 丘脑胆囊收缩素免疫反应性传入神经的退化。

DOI：
发表时间：
2004
期刊：
Brain Research 1022
影响因子：
0
作者：
Ohara S;Ukita Y;Ninomiya H;Ohno K.
通讯作者：
Ohno K.

Novel TSC2 mutations and decreased expression of tuberin in cultured tumor cells with an insertion mutation

具有插入突变的培养肿瘤细胞中新的 TSC2 突变和马铃薯蛋白表达降低

DOI：
发表时间：
2004
期刊：
HUMAN MUTATION #696(Online)
影响因子：
0
作者：
Feng J-H;Yamamoto T;Nanba E;Ninomiya H. Oka A. Ohno K
通讯作者：
Ninomiya H. Oka A. Ohno K

Endosomal accumulation of Toll-like receptor 4 causes constitutive secretion of cytokines and activation of STATs in Niemann-Pick disease type C fibroblasts : a potential basis for glial cell activation in the NPC brain.

Toll 样受体 4 的内体积累导致尼曼匹克病 C 型成纤维细胞中细胞因子的组成性分泌和 STAT 的激活：NPC 大脑中胶质细胞激活的潜在基础。

DOI：
发表时间：
2007
期刊：
J Neurosci 27
影响因子：
0
作者：
Suzuki M;Sugimoto Y;Ohsaki Y;Ueno M;Kato S;Kitamura Y;Hosokawa H;Davies JP;Ioannou YA;Vanier MT;Ohno K;Ninomiya H.
通讯作者：
Ninomiya H.

今日の小児治療指針第14版「Niemann-Pick病」(大関武彦、古川漸、横田俊一郎編)

今日儿科治疗指南第14版《尼曼-匹克病》（大关武彦、古川进、横田俊一郎主编）