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Analysis of the Pathogenesis of Familial Amyloidotic Polyneuropathy (FAP) -Application of Transgenic mice of FAP-

家族性淀粉样多发性神经病（FAP）发病机制分析-FAP转基因小鼠的应用-

基本信息

批准号：
01570452
负责人：
ARAKI Shukuro
金额：
$ 1.34万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1990
项目状态：
已结题

项目摘要

We have been analyzing the physiochemical aspects of the transgenic mice with variant transthyretin gene, which is considered to be a model of Familial Amyloidotic Polyneuropathy (FAP), to know the pathogenesis of FAP. The following is the results.1. We have been keeping 100 of the pure transgenic mice with variant transthyretin gene screened by DNA analysis and immunoblotting method.2. We exsanguinated these mice every month and examined the amyloid deposition of each tissues in the autopsied transgenic mice. We found that the amyloid deposition was recognized in the small intestine, kidney, heart, thyroid and systemic small vessels of the mice from the age of 6 months. The amyloid fibrils found in these tissues were stained by anti-human TTR antibody, which was seemed to be derived from injected human mutant TTR gene. Electronmicroscopic analysis revealed that the structure of the amyloid fibrils was very similar to that in the human amyloid fibrils. However, no amyloid deposition wa … More s detected in the peripheral nerves and no pathological changes were found in these nerves.3. Analysis of purified amylold fibrils from the kidney of the transgenic mice by SDS electrophoresis revealed that major protein was detected in 15 KD band which is similar to that of TTR. According to the immunoblotting analysis, this amyloid fibril reacted with human TTR, not with anti-mice SAA. These results suggest that amyloid fibrils purified from the transgenic mice may be almost the same as those in FAP patients.4. To elucidate the role of Serum Amyloid P component (SAP), which is one of the major constituents of amyloid fibrils, we examined the starting period of amyloid deposition of the transgenic mice after inducing the peritonitis by injecting endotoxin. However, no remarkable changes were found in the amyloid deposited tissues and starting period of amyloid deposition in these mice.From these results, we concluded that mutant TTR is indispensable to show the onset of FAP and this transgenic mice is very useful to elucidate the pathogenesis of FAP. Moreover, we will evaluate the effect of the environmental factor (s), such as temperature, food and some toxins. Less

本研究通过对转甲状腺素运载蛋白基因小鼠的理化指标进行分析，探讨FAP的发病机制。以下是结果。通过DNA分析和免疫印迹法筛选出100只转甲状腺素运载蛋白基因纯系小鼠.我们每个月对这些转基因小鼠进行放血，并检查尸检转基因小鼠中每个组织的淀粉样蛋白沉积。我们发现，淀粉样蛋白沉积在小肠，肾脏，心脏，甲状腺和全身小血管的小鼠从6个月的年龄。用抗人TTR抗体对这些组织中发现的淀粉样纤维进行染色，该抗体似乎来源于注射的人突变TTR基因。电镜分析显示，淀粉样纤维的结构与人淀粉样纤维非常相似。然而，没有淀粉样蛋白沉积， ...更多信息周围神经中检测到S，未见病理改变. SDS电泳分析转基因小鼠肾脏淀粉样纤维的主要蛋白质在15KD处，与TTR相似。根据免疫印迹分析，该淀粉样纤维与人TTR反应，而不与抗小鼠SAA反应。这些结果表明，从转基因小鼠中纯化的淀粉样纤维可能与FAP患者中的淀粉样纤维几乎相同.为了阐明血清淀粉样蛋白P组分（SAP）的作用，SAP是淀粉样蛋白纤维的主要成分之一，我们检查了转基因小鼠在通过注射内毒素诱导腹膜炎后淀粉样蛋白沉积的起始时期。结果表明，突变型TTR是FAP发病的重要标志，该转基因小鼠对FAP发病机制的研究具有重要意义。此外，我们将评估环境因素的影响，如温度，食物和一些毒素。少