Develpment of a new method to revent amyloid formation in genetically engineered mice.
开发一种新方法来阻止基因工程小鼠中淀粉样蛋白的形成。
基本信息
- 批准号:13470509
- 负责人:
- 金额:$ 8.77万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (B)
- 财政年份:2001
- 资助国家:日本
- 起止时间:2001 至 2003
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Familial amyloidotic polyneuropathy is an autosomal dominant disorder characterized by peripheral and sutonomic polyneuropathy. This disease was caused by the mutation in the transthyretin (ttr) gene, leading to systemic amyloidosis Amyloidogenic processes include dissociation of ttr tetramers into monomers, modification of monomers, aggregation of monomers, formation of amyloid fibrils, and attachment of serum amyloid P component (SAP) to amyloid fibrils. To elucidate the factors involved in these steps and to devise a new way of treatment, we tried to develop a casette exchnageable mouse using Cre-mutant lox system which was developed by ourselves. We made a vector for homologous recombination in ES cells, consisting of DT-A, 2.6 kb of homologous region of ttr, lox71, PGK-neo, loxP, poly A, lox2272, and 7.9kb homologous region of ttr. We produce chimeric mice that are now mating with female mice. To analyze the effects of intestinal flora, we transferred intestinal flora from SPF mic … More e as well as conventional mice housed in two different facilities 1 and 2 to transgenic mice. We found that amyloid was deposited in alimentary tract of transgenic mice transferred from conventional 2, but not from SPF and conventional 1, and that in conventional 2 condition symbiotes were decreased accompanied by an increase of weak pathogens while keeping. These suggest that intestinal flora can affect the amyloid deposition in alimentary tract. On the other hand, it is proposed that disulfide bond between cystein residues at position 10 in ttr molecule is prerequisite for aggregation of monomer. To test this possibility, we produce transgenic mice by introducing mutant ttr gene containing serine and methionine residues at position 10 and 30, respectively. Surprisingly, we could not observe amyloid deposition in these transgenic mice, although amyloid deposition was observed in transgenic mice carrying a mutant ttr gene carrying methionine at position 30. These results suggest that cystein residue at position 10 will be important for monomers to aggregate each other. We also tested whether CPHPC developed by Pepys et al. can remove SAP from serum and amyloid fibrils. We found that SAP was effectively removed from serum and amyloid deposits using transgenic mice carrying human SAP gene Less
家族性淀粉样变性多神经病变是一种常染色体显性遗传病,其特征是周围神经病变和周围神经病变。这种疾病是由转甲状腺素(ttr)基因突变引起的,导致系统性淀粉样变性。淀粉样变性过程包括ttr四聚体解离成单体、单体修饰、单体聚集、淀粉样原纤维形成以及血清淀粉样蛋白P组分(SAP)附着在淀粉样原纤维上。为了阐明这些步骤中涉及的因素,并设计一种新的治疗方法,我们尝试使用自己开发的cre突变体lox系统来开发可交换小鼠。我们制作了一个用于ES细胞同源重组的载体,由DT-A、ttr、lox71、PGK-neo、loxP、poly a、lox2272和ttr的7.9kb同源区组成。我们培育出嵌合老鼠,现在它们正在与雌鼠交配。为了分析转基因小鼠肠道菌群的影响,我们将SPF mic . More e和饲养在不同设施1和2中的普通小鼠的肠道菌群转移到转基因小鼠身上。我们发现常规2转基因小鼠的消化道中有淀粉样蛋白沉积,而SPF和常规1转基因小鼠的消化道中没有淀粉样蛋白沉积,常规2条件下共生菌减少,弱病原体增加。提示肠道菌群可影响淀粉样蛋白在消化道的沉积。另一方面,提出ttr分子中第10位半胱氨酸残基之间的二硫键是单体聚集的先决条件。为了验证这种可能性,我们通过引入分别在第10位和第30位含有丝氨酸和蛋氨酸残基的突变ttr基因来生产转基因小鼠。令人惊讶的是,我们没有在这些转基因小鼠中观察到淀粉样蛋白沉积,尽管在携带30号位置携带蛋氨酸的突变ttr基因的转基因小鼠中观察到淀粉样蛋白沉积。这些结果表明,第10位的半胱氨酸残基对于单体相互聚集是重要的。我们还测试了Pepys等人开发的CPHPC是否可以从血清和淀粉样原纤维中去除SAP。我们发现,使用携带人类SAP基因Less的转基因小鼠可以有效地从血清和淀粉样蛋白沉积物中去除SAP
项目成果
期刊论文数量(42)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
山村研一: "ゲノム医学に役立つ個体モデル"日本炎症・再生医学雑誌. 23. 269-274 (2003)
Kenichi Yamamura:“对基因组医学有用的个体模型”日本炎症和再生医学杂志 23. 269-274 (2003)。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Noguchi, H. et al.: "Effect of the intestinal Flora on amyloid deposition in a transgenic mouse model of familial amyloidotic polyneuropathy."Exp.Anim.. 51. 309-316 (2002)
Noguchi, H. 等人:“家族性淀粉样多发性神经病转基因小鼠模型中肠道菌群对淀粉样蛋白沉积的影响。”Exp.Anim.. 51. 309-316 (2002)
- DOI:
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- 影响因子:0
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Hoshino, T. et al.: "IL-18 transgenic mice : in vivo evidence of a broad role for IL-18 in modulating immune function"J. Immunol. 14. 7014-7018 (2001)
Hoshino, T. 等人:“IL-18 转基因小鼠:IL-18 在调节免疫功能中广泛作用的体内证据”J.
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- 发表时间:
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- 影响因子:0
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Takaoka, Y., Ohta, M., Miyakawa, K., Nakamura, O., Suzuki, M., Takahashi, K., Yamamura, K., Sakaki, Y.: "Cysteine 10 is a Key Residue in Amyloidogenesis of Human Transthyretin Val30Met."Amr.J.Pathol.. 164. 337-345 (2004)
Takaoka, Y.、Ohta, M.、Miyakawa, K.、Nakamura, O.、Suzuki, M.、Takahashi, K.、Yamamura, K.、Sakaki, Y.:“半胱氨酸 10 是淀粉样蛋白生成中的关键残基
- DOI:
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- 影响因子:0
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浅島誠, 山村研一編集: "生命工学新しい生命へのアプローチ"共立出版. 298 (2002)
Makoto Asashima 和 Kenichi Yamamura 编辑:“新生命的生物技术方法”Kyoritsu Shuppan 298 (2002)。
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- 影响因子:0
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YAMAMURA Kenichi其他文献
YAMAMURA Kenichi的其他文献
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{{ truncateString('YAMAMURA Kenichi', 18)}}的其他基金
Frontier studies in development and cancer
发育和癌症的前沿研究
- 批准号:
17012018 - 财政年份:2005
- 资助金额:
$ 8.77万 - 项目类别:
Grant-in-Aid for Scientific Research on Priority Areas
Analysis on genetic and environmental factors using a mouse model for dominantly inherited disease
使用显性遗传病小鼠模型分析遗传和环境因素
- 批准号:
17200028 - 财政年份:2005
- 资助金额:
$ 8.77万 - 项目类别:
Grant-in-Aid for Scientific Research (A)
Integrated cancer research using in vivo models
使用体内模型的综合癌症研究
- 批准号:
17012017 - 财政年份:2005
- 资助金额:
$ 8.77万 - 项目类别:
Grant-in-Aid for Scientific Research on Priority Areas
DEVELOPMENT OF MHV-RESISTANT MOUSE USING RNAi TRAP METHOD
利用 RNAi TRAP 方法开发抗 MHV 小鼠
- 批准号:
13558098 - 财政年份:2001
- 资助金额:
$ 8.77万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
IDENTIFICATION OF DISEASE GENE USING BAC TRANSGENIC MICE
利用 BAC 转基因小鼠鉴定疾病基因
- 批准号:
11694296 - 财政年份:1999
- 资助金额:
$ 8.77万 - 项目类别:
Grant-in-Aid for Scientific Research (B).
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 - 财政年份:1998
- 资助金额:
$ 8.77万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
DEVELOPEMNT OF TRANSGENIC TECHNOLOGY AND IT'S USE FOR CANCER RESEARCH
转基因技术的发展及其在癌症研究中的应用
- 批准号:
09253243 - 财政年份:1997
- 资助金额:
$ 8.77万 - 项目类别:
Grant-in-Aid for Scientific Research on Priority Areas
PRODUCTION OF MUTANT MICE AND ESTABLISHMENT OF EMBRYO BANK
突变小鼠的产生及胚胎库的建立
- 批准号:
07558115 - 财政年份:1995
- 资助金额:
$ 8.77万 - 项目类别:
Grant-in-Aid for Scientific Research (A)
MOLECULAR MECAHNISMS OF ENDODERM DIFFERENTIATION
内胚层分化的分子机制
- 批准号:
07457555 - 财政年份:1995
- 资助金额:
$ 8.77万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
PRODUCTION OF MOUSE MODELS FOR MALFORMATION BY GENE TRAP
基因陷阱致畸小鼠模型的制作
- 批准号:
04454578 - 财政年份:1992
- 资助金额:
$ 8.77万 - 项目类别:
Grant-in-Aid for General Scientific Research (B)
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