DEVELOPMENT OF PREVENTION METHOD USING A MOUSE MODEL FOR FAMILIAL AMYLOIDOTIC POLYNEUROPATHY

使用小鼠模型开发家族性淀粉样多发性神经病的预防方法

• 批准号: 10470506
• 负责人: YAMAMURA Kenichi
• 金额: $ 8.19万
• 依托单位: KUMAMOTO UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10470506/
• 关键词: AMYLOIDOSIS; TRANSGENIC MOUSE; TRANSTHYRETIN; ANTIOXIDANT; FAP; 家族性アミロイドポリニューロパシー

Familial amyloidotic polyneuropathy (FAP) is an autosomal, dominant disorder characterized by extracellular deposition of fibrillar amyloid protein and prominent peripheral nerve involvement. In most patients with Type I FAP, the major component of the amyloid deposits is a variant TTR with a substitution of methionine for valine at amino acid position 30 (hMet30). All FAP patients so far examined have been found carry at least one mutant gene, suggesting that this disease is mainly caused by the presence of the mutant TTR gene. However, the pathologic processes of amyloid deposition in FAP remain totally unknown. Thus, liver transplantation is the only effective treatment. We previously demonstrated that a mouse line carrying a human Met30 TTR gene developed amyloid deposition in various tissues as in FAP patients except peripheral nervous tissues. Using these transgenic mice, we demonstrated that both genetic and environmental factors are involved in the development of amyloid. As in … More testinal flora was suggested to be one of these factors, we established transgenic mouse lines having either flora from SPF mouse or conventional mouse. In addition, we tried to investigate the role of Cys10, because the disulfide bond between Cys residues on adjuscent trasnthyretin molecules was suggested to be important for amyloidogenesis. We produced three lines of transgenic mouse lines carrying one of the transgenes, Cys10-Val30, Cys10-Met30, or Ser10-Met30 to test this possibility. As expected, no amyloid deposition was observed in 23 transgenic mice carrying the noramal allel, Cys10-Val30. However, amyloid was observed in 6 out of 19 mice carrying the mutant gene, Cys10-Met30. Interestingly, we found amyloid deposits only in 1 out of 37 transgenic mice carrying Ser10-Met30. These result clearly suggest that cystein at position 30 plays an important role in amyloid formation. Based on this result, we are analyzing whether anti-oxidant can reduce the amount of amyloid in a transgenic mouse model. Less

家族性淀粉样变性多发性神经病(FAP)是一种常染色体显性遗传性疾病，其特征是纤维淀粉样蛋白在细胞外沉积，并明显累及周围神经。在大多数I型FAP患者中，淀粉样蛋白沉积的主要成分是一个变异的TTR，在30位氨基酸(HMet30)上用蛋氨酸取代了Valine。到目前为止，所有接受检查的FAP患者都被发现携带至少一个突变基因，这表明这种疾病主要是由突变的TTR基因的存在引起的。然而，FAP中淀粉样蛋白沉积的病理过程仍完全不清楚。因此，肝移植是唯一有效的治疗方法。我们之前曾证明，携带人类Met30 TTR基因的小鼠在除周围神经组织外的各种组织中都出现了淀粉样蛋白沉积，就像FAP患者一样。利用这些转基因小鼠，我们证明了遗传和环境因素都参与了淀粉样蛋白的发育。就像在…中更多的肠道菌群被认为是这些因素之一，我们建立了含有SPF小鼠和常规小鼠菌群的转基因小鼠系。此外，我们试图研究Cys10的作用，因为调节反式甲状腺激素分子上的Cys残基之间的二硫键被认为对淀粉样蛋白的发生是重要的。我们生产了三个转基因小鼠品系，携带其中一个转基因，Cys10-Val30，Cys10-Met30，或Ser10-Met30来测试这种可能性。正如预期的那样，在23只携带正常等位基因Cys10-Val30的转基因小鼠中没有观察到淀粉样蛋白沉积。然而，在19只携带突变基因Cys10-Met30的小鼠中，有6只观察到淀粉样蛋白。有趣的是，我们只在37只携带Ser10-Met30的转基因小鼠中发现了淀粉样蛋白沉积。这些结果清楚地表明，30位半胱氨酸在淀粉样蛋白的形成中起着重要作用。基于这一结果，我们正在分析抗氧化剂是否可以减少转基因小鼠模型中淀粉样蛋白的数量。较少

项目成果

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