Molecular pathogenesis of dialysis-related amyloidosis-A fusion of the in vitro model and the animal model-

• Project/Area Number: 18390120
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: University of Fukui
• Principal Investigator: NAIKI Hironobu University of Fukui, 医学部, 教授 (10227704)
• Co-Investigator(Kenkyū-buntansha): HASEGAWA Kazuhiro 福井大学, 医学部, 助教 (60324159) ; OOKOSHI Tadakazu 福井大学, 医学部, 助教 (90362037) ; HIGUCH Keiichi 信州大学, 大学院・医学研究科, 教授 (20173156) ; GOTO Yuji 大阪大学, 蛋白質研究所, 教授 (40153770)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥16,680,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥1,980,000); Fiscal Year 2008: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2007: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2006: ¥8,100,000 (Direct Cost: ¥8,100,000)
• Keywords: 透析アミロイドーシス / β2-ミクログロブリン / アミロイド線維 / 試験管内分子間相互作用 / トランスジェニックマウス / 透析アミロイド症 / 病理学 / トランジェニックマウス

Research Abstract

本研究でわれわれは、長期血液透析患者に発症するβ2-ミクログロブリン(β2-m)アミロイドーシス発症の分子機構解明を目指し、リゾフォスファチジン酸など一部のリゾリン脂質、各種遊離脂肪酸等、陰性荷電を有する生体界面活性分子が、生理的条件下におるβ2-mアミロイド線維の試験管内伸長反応を促進することを明らかにした。また、モデル動物の確立を目指し、ヒトβ2-mトランスジェニックマウスを作成した。

Research Products

• [Journal Article] A comprehensive model for packing and hydration for amyloid fibrils of β2-microglobulin (2009)
  • Author(s): Lee, Y-H., Chatani, E., Sasahara, K., Naiki, H., Goto, Y.
  • Journal Title: J. Biol. Chem 284(4) Pages: 2169-2175
  • NAID: 120006557647
• [Journal Article] Destruction of amyloid fibrils of a β2-microgobulin fragment by laser beam irradiation (2009)
  • Author(s): Ozawa, D., Yagi, H., Ban, T.Kameda, A., Kawakami,T., Naiki, H., Goto, Y.
  • Journal Title: J. Biol. Chem 284(2) Pages: 1009-1017
• [Journal Article] Destruction of amyloid fibrils of a β_2-microglobulin fragment by laser beam irradiation (2009)
  • Author(s): Ozawa, D., et al.
  • Journal Title: J. Biol. Chem. 284 Pages: 1009-1017
  • Peer Reviewed
• [Journal Article] A comprehensive model for packing and hydration for amyloid fibrils of β_2-microglobulin (2009)
  • Author(s): Lee, YH., et al.
  • Journal Title: J. Biol. Chem. 284 Pages: 2169-2175
  • Peer Reviewed
• [Journal Article] アミロイド線維の形成・沈着機構-重合核依存性重合モデルを中心に- (2009)
  • Author(s): 内木宏延, 他
  • Journal Title: 神経内科 70 Pages: 129-135
• [Journal Article] Growth of β2-microglobulin-related amyloid fibrils by non-esterified fatty acids at a neutral pH (2008)
  • Author(s): Hasegawa, K., Tsutsumi-Yasuhara, S., Ookoshi, T., Ohhashi,Y., Kimura, H., Takahashi, N., Yoshida, H., Miyazaki, R., Goto, Y., Naiki, H.
  • Journal Title: Biochem.J 416(2) Pages: 307-315
• [Journal Article] Lysophospholipids induce the nucleation and extension of β2-microglobulin-related amyloid fibrils at a neutral pH (2008)
  • Author(s): Ookoshi, T. Hasegawa, K., Ohhashi, Y., Kimura, H., Takahashi, N., Yoshida, H., Miyazaki, R., Goto, Y., Naiki, H.
  • Journal Title: Nephrol. Dial. Transplant 23(10) Pages: 3247-3255
• [Journal Article] Procollagen C-proteinase enhancer-1(PCPE-1)interacts with β2-microglobulin(β2-m)and may help initiate β2-m amyloid fibril formation in connective tissues (2008)
  • Author(s): Morimoto, H., Wada, J., Font, B., Mott, J.D., Hulmes D.J., Ookoshi, T., Naiki, H., Yasuhara, A., Nakatsuka, A., Fukuoka, K., Takatori, Y., Ichikawa, H., Akagi, S., Nakao, K., Makino, H.
  • Journal Title: Matrix Biol 27(3) Pages: 211-219
• [Journal Article] Kinetic coupling of folding and prolyl isomerization of β_2-nicroglobulin studied by mutational analysis (2008)
  • Author(s): Sakata, M., et al.
  • Journal Title: J. Mol. Biol. 382 Pages: 1242-1255
  • Peer Reviewed
• [Journal Article] Growth of β_2-microglobulin-related amyloid fibrils by non-esterified fatty acids at a neutral pH (2008)
  • Author(s): Hasegawa, K., et al.
  • Journal Title: Biochem. J. 416 Pages: 307-315
  • Peer Reviewed
• [Journal Article] アミロイド (2008)
  • Author(s): 内木宏延
  • Journal Title: 蛋白質核酸酵素 53 Pages: 906-906
• [Journal Article] チオフラビンT (2008)
  • Author(s): 内木宏延
  • Journal Title: 蛋白質核酸酵素 53 Pages: 968-968
• [Journal Article] β_2-ミクログロブリンのアミロイド線維化 (2008)
  • Author(s): 大越忠和, 他
  • Journal Title: 腎と骨代謝 22 Pages: 7-12
• [Journal Article] Procollagen C-proteinase enhancer-1(PCPE-1)interacts with β_2-microglobulin(β2-m)and may help initiate β2-m amyloid fibril formation in connective tissues (2008)
  • Author(s): Morimoto, H., et. al.
  • Journal Title: Matrix Biol. 27 Pages: 211-219
  • Peer Reviewed
• [Journal Article] Thiol compounds inhibit the formation of amyloid fibrils by β_2-microglobulin at neutral pH (2008)
  • Author(s): Yamamoto, K., et. al.
  • Journal Title: J. Mol. Biol. 376 Pages: 258-268
  • Peer Reviewed
• [Journal Article] Amyloid nucleation triggered by agitation of β_2-microglobulinunder acidic and neutral pH conditions (2008)
  • Author(s): Sasahara, K., et. al.
  • Journal Title: Biochemistry 47 Pages: 2650-2660
  • Peer Reviewed
• [Journal Article] Visualization and classification of amyloid β supramolecular assemblies (2007)
  • Author(s): Yagi, H., Ban, T. Morigaki, K., Naiki, H., Goto, Y.
  • Journal Title: Biochemistry 46(51) Pages: 15009-15017
• [Journal Article] Cross-seeding and cross-competition in mouse apolipoprotein A-II amyloid fibrils and protein A amyloid fibrils (2007)
  • Author(s): Yan, J., Fu, X., Ge, F., Zhang, B., Yao, J., Zhang, H., Qian, J., Tomozawa, H., Naiki, H., Sawashita, J., Mori, M., Higuchi, K.
  • Journal Title: Am.J.Pathol 171(1) Pages: 172-180
• [Journal Article] A toxic monomeric conformer of the polyglutamine protein. (2007)
  • Author(s): Nagai, Y., Inui, T., Popiel, H.A., Fujikake, N., Hasegawa, K., Urade, Y., Goto, Y., Naiki, H., Toda, T.
  • Journal Title: Nat. Struct. Mol. Biol 14(4) Pages: 332-340
• [Journal Article] The anti-amyloidogenic effect is exerted against Alzheimer's β-amyloid fibrils in vitro by preferential and reversible binding of flavonoids to the amyloid fibril structure (2007)
  • Author(s): Hirohata, M., Hasegawa, K., Tsutsumi-Yasuhara, S., Ohhashi, Y., Ookoshi, T., Ono, K., Yamada, M., Naiki, H.
  • Journal Title: Biochemistry 46(7) Pages: 1888-1899
• [Journal Article] Inhibitors of amyloid β-protein aggregation mediated by GM1-containing raft-like membranes (2007)
  • Author(s): Matsuzaki, K., Noguch, T., Wakabayashi, M., Ikeda, K., Okada, T., Ohashi, Y., Hoshino, M., Naiki, H.
  • Journal Title: Biochim. Biophys. Acta-Biomembranes 1768(1) Pages: 122-130
• [Journal Article] A toxic monomeric conformer of the polyglutamine protein (2007)
  • Author(s): Nagai, Y., et. al.
  • Journal Title: Nat. Struct. Mol. Biol. 14 Pages: 332-340
  • Peer Reviewed
• [Journal Article] Cross-seeding and cross-competition in mouse apolipoprotein A-II amyloid fibrils and protein A amyloid fibrils (2007)
  • Author(s): Yan, J., et. al.
  • Journal Title: Am. J. Pathol. 171 Pages: 172-180
  • Peer Reviewed
• [Journal Article] Heat-induced conversion of β_2-microglobulin and hen egg-white lysozyme into amyloid fibrils (2007)
  • Author(s): Sasahara, K., et. al.
  • Journal Title: J. Mol. Biol. 372 Pages: 981-991
  • Peer Reviewed
• [Journal Article] Visualization and Classification of Amyloid β Supramolecular Assemblies (2007)
  • Author(s): Yagi, H., et. al.
  • Journal Title: Biochemistry 46 Pages: 15009-15017
  • Peer Reviewed
• [Journal Article] 透析アミロイドーシス-基礎研究から治療戦略Update- (2007)
  • Author(s): 内木 宏延, 他
  • Journal Title: 透析会誌 40 Pages: 1025-1025
• [Journal Article] β_2-ミクログロブリンアミロイド線維形成・沈着の分子機構 (2007)
  • Author(s): 山本 卓, 他
  • Journal Title: 透析会誌 40 Pages: 1028-1030
• [Journal Article] ポリフェノールがβアミロイド蛋白凝集に及ぼす抗アミロイド効果の分子機構解明 (2007)
  • Author(s): 廣畑 美枝, 他
  • Journal Title: 未病と抗老化 16 Pages: 115-127
• [Journal Article] Inhibitors of amyloid β-protein aggregation mediated by GM1-containing raft-like membranes. (2007)
  • Author(s): Matsuzaki, K. et al.
  • Journal Title: Biochim.Biophys.Acta 1768(1) Pages: 122-130
• [Journal Article] Cerebrospinal fluid of Alzheimer's disease and dementia with Lewy bodies patients enhances α-synuclein fibril formation in vitro. (2007)
  • Author(s): Ono, K.et al.
  • Journal Title: Exp.Neurol. 203(2) Pages: 579-583
• [Journal Article] The anti-amyloidogenic effect is exerted against Alzheimer's β-amyloid fibrils in vitro by preferential and reversible binding of flavonoids to the amyloid fibril structure. (2007)
  • Author(s): Hirohata, M. et al.
  • Journal Title: Biochemistry 46(7) Pages: 1888-1899
• [Journal Article] Flow-induced alignment of amyloid protofilaments revealed by linear dichroism. (2007)
  • Author(s): Adachi, R. et al.
  • Journal Title: J.Biol.Chem. 282(12) Pages: 8978-8983
• [Journal Article] Heat-triggered conversion of protofibrils into mature amyloid fibrils of β_2-microglobulin. (2007)
  • Author(s): Sasahara, K. et al.
  • Journal Title: Biochemistry 46(11) Pages: 3286-3293
• [Journal Article] 3D structure of amyloid protofilaments of β2-microglobulin fragment probed by solid-state NMR (2006)
  • Author(s): Iwata, K., Fujiwara, T., Matsuki, Y., Akutsu, H., Takahashi, S., Naiki, H., Goto, Y.
  • Journal Title: Proc. Natl. Acad. Sci. U.S.A. 103(48) Pages: 18119-18124
• [Journal Article] Real-time and single fibril observation of the formation of amyloid β spherulitic structures (2006)
  • Author(s): Ban, T., Morigaki, K., Yagi, H., Kawasaki, T., Kobayashi, A., Yuba, S., Naiki, H., Goto, Y.
  • Journal Title: J.Biol.Chem 281(44) Pages: 33677-33683
  • NAID: 120006557651
• [Journal Article] Conformation of amyloid fibrils of β2-microglobulin probed by tryptophan mutagenesis (2006)
  • Author(s): Kihara, M., Chatani, E., Iwata, K., Yamamoto, K., Matsuura, T., Nakagawa, A., Naiki, H., Goto, Y.
  • Journal Title: J.Biol.Chem 281(41) Pages: 31061-31069
  • NAID: 120006557652
• [Journal Article] Seeding-dependent propagation and maturation of β_2-microglobulin amyloid fibrils under high pressure (2006)
  • Author(s): Chatani, E., Naiki, H., Goto, Y.
  • Journal Title: J. Mol. Biol 359(4) Pages: 1086-1096
• [Journal Article] Anti-amyloidogenic effects of antioxidants : Implications for the prevention and therapeutics of Alzheimer's disease. (2006)
  • Author(s): Ono, K.et al.
  • Journal Title: Biochim. Biophys. Acta 1762(6) Pages: 575-586
• [Journal Article] Seeding-dependent propagation and maturation of β_2-microglobulin amyloid fibrils under high pressure. (2006)
  • Author(s): Chatani, E. et al.
  • Journal Title: J.Mol.Biol. 359(4) Pages: 1086-1096
• [Journal Article] Exothermic effects observed upon heating of β_2-microglobulin monomers in the presence of amyloid seeds. (2006)
  • Author(s): Sasahara, K. et al.
  • Journal Title: Biochemistry 45(29) Pages: 8760-8769
• [Journal Article] Conformation of amyloid fibrils of β_2-microglobulin probed by tryptophan mutagenesis. (2006)
  • Author(s): Kihara, M. et al.
  • Journal Title: J.Biol.Chem. 281(41) Pages: 31061-31069
• [Journal Article] Mechanism by which the amyloid-like fibrils of a β_2-microglobulin fragment are induced by fluorine-substituted alcohols. (2006)
  • Author(s): Yamaguchi, KI. et al.
  • Journal Title: J.Mol.Biol. 363(1) Pages: 279-288
• [Journal Article] Blood-borne factors inhibit Alzheimer's β-amyloid fibril formation in vitro. (2006)
  • Author(s): Ono, K.et al.
  • Journal Title: Exp.Neurol. 202(1) Pages: 125-132
• [Journal Article] Real-time and single fibril observation of the formation of amyloid β spherulitic structures. (2006)
  • Author(s): Ban, T.et al.
  • Journal Title: J.Biol.Chem. 281(44) Pages: 33677-33683
• [Journal Article] 3D structure of amyloid protofilaments of β_2-microglobulin fragment probed by solid-state NMR. (2006)
  • Author(s): Iwata, K. et al.
  • Journal Title: Proc.Natl.Acad.Sci.U.S.A. 103(48) Pages: 18119-18124
• [Journal Article] The development of preventives and therapeutics for Alzheimer's disease that inhibit the formation of β-amyloid fibrils (fAβ), as well as destabilize preformed fAβ. (2006)
  • Author(s): Ono, K.et al.
  • Journal Title: Curr.Pharm.Des. 12(33) Pages: 4357-4375
• [Journal Article] Lysophospholipids Induce the Nucleation and Extension of β2-Microglobulin-Related Amyloid Fibrils at a Neutral pH
  • Author(s): Ookoshi, T., et. al.
  • Journal Title: Nephrol. Dial. Transplant. (in press)
  • Peer Reviewed
• [Presentation] アミロイド線維形成の重合核依存性重合モデルと線維形成阻害薬の探索 (2009)
  • Author(s): 内木宏延, 長谷川一浩, 小野賢二郎, 山田正仁
  • Organizer: 日本薬学会第129年会シンポジウム(S-22)「アミロイドβペプチドの凝集・毒性発現の分子メカニズムの解明と低分子化合物による阻害 : アルツハイマー病の克服に向けて」
  • Place of Presentation: 京都
• [Presentation] アミロイド線維形成の重合核依存性重合モデルと線維形成阻害薬の探索 (2009)
  • Author(s): 内木宏延, 他
  • Organizer: 日本薬学会第129年会
  • Place of Presentation: 京都
• [Presentation] アミロイド線維形成・沈着の分子機構-ALアミロイドーシスを中心に- (2008)
  • Author(s): 内木宏延
  • Organizer: 第9回東京腎炎・ネフローゼ研究会
  • Place of Presentation: 東京
  • Year and Date: 2008-07-26
• [Presentation] ヒトアミロイドーシスの分子病態解明に向けて (2008)
  • Author(s): 内木宏延
  • Organizer: 日本ヒトプロテオーム機構第6回大会シンポジウム「蛋白質のフォールディング病」
  • Place of Presentation: 大阪
• [Presentation] ヒトアミロイドーシスの分子病態解明に向けて : 現状と展望 (2008)
  • Author(s): 内木宏延
  • Organizer: 第8回日本蛋白質科学会年会シンポジウム「アミロイド構造生物学の新たな地平」
  • Place of Presentation: 東京
• [Presentation] リソリン脂質のβ2-ミクログロブリンアミロイド線維伸長促進効果(II)-透析患者血漿を用いた検討 (2008)
  • Author(s): 大越忠和, 他
  • Organizer: 第97回日本病理学会総会
  • Place of Presentation: 金沢
• [Presentation] ヒトアミロイドーシスの分子病態解明に向けて : 現状と展望 (2008)
  • Author(s): 内木宏延
  • Organizer: 第8回日本蛋白質科学会年会
  • Place of Presentation: 東京
• [Presentation] ヒトアミロイドーシスの分子病態解明に向けて (2008)
  • Author(s): 内木宏延
  • Organizer: 日本ヒトプロテオーム機構第6回大会
  • Place of Presentation: 大阪
• [Presentation] The relationship between plasma concentrations of lysopholipids (LPLs) and dialysis related amyloidosis in hemodialysis patients (2008)
  • Author(s): Takahashi, N., et al.
  • Organizer: 41th American Society of Nephrology Annual Meeting
  • Place of Presentation: Philadelphia
• [Presentation] 血漿リソリン脂質の透析アミロイド形成における意義 (2008)
  • Author(s): 高橋直生, 他
  • Organizer: 第55回日本臨床検査医学会学術集会
  • Place of Presentation: 名古屋
• [Presentation] Uniforming the molecular weight of amyloid fibrils by ultrasonication (2007)
  • Author(s): 茶谷 絵理, 他
  • Organizer: 日本生物物理学会第45回年会
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-23
• [Presentation] The effects of reductant on the amyloid fibril formation of β2-microglobulin (2007)
  • Author(s): 山本 香織, 他
  • Organizer: 日本生物物理学会第45回年会
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-23
• [Presentation] Packing density of amyloid-like and amyloid fibrils (2007)
  • Author(s): 李 映昊, 他
  • Organizer: 日本生物物理学会第45回年会
  • Place of Presentation: 横浜
  • Year and Date: 2007-12-23
• [Presentation] Polyphenolsがβアミロイド線維に及ぼす抗アミロイド効果の分子機構解明 (2007)
  • Author(s): 廣畑 美枝, 他
  • Organizer: 第48回日本神経学会総会
  • Place of Presentation: 名古屋
• [Presentation] 透析アミロイド症病態解明へのアプローチupdate (2007)
  • Author(s): 山本 卓, 他
  • Organizer: 第52回日本透析医学会学術集会・総会
  • Place of Presentation: 大阪市
• [Presentation] Molecular pathogenesis of β2-microglobulin-related amyloidosis (2006)
  • Author(s): Naiki, H.
  • Organizer: 24th Annual Meeting of the International Society of Blood Purification
  • Place of Presentation: Nara, Japan
• [Book] タンパク質の事典(編 : 猪飼篤, 伏見譲, 卜部格, 上野川修一, 中村春木, 浜窪隆雄),"アミロイドタンパク質" (2008)
  • Author(s): 内木宏延(分担執筆)
  • Publisher: 朝倉書店
• [Book] タンパク質の事典 (2008)
  • Author(s): 内木宏延
  • Total Pages: 863
  • Publisher: 朝倉書店