フォールディング病に対する新たな治療原理の確立

• 研究課題/領域番号: 19390045
• 研究種目: 基盤研究(B)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 医療系薬学
• 研究機関: 熊本大学
• 研究代表者: 甲斐 広文 熊本大学, 大学院・生命科学研究部, 教授 (30194658)
• 研究分担者: 首藤 剛 熊本大学, 大学院・医学薬学研究部, 助手 (80333524) ; スイコ メリー・アン・ソテン 熊本大学, 大学院・医学薬学研究部, 助教 (20363525)
• 連携研究者: 首藤 剛 熊本大学, 大学院・生命科学研究部, 講師 (80333524) ; スイコ・メリー アン・ソテン 熊本大学, 大学院・生命科学研究部, 助教 (20363525)
• 研究期間 (年度): 2007 – 2009
• 研究課題ステータス: 完了 (2009年度)
• 配分額: 18,980千円 (直接経費: 14,600千円、間接経費: 4,380千円); 2009年度: 5,720千円 (直接経費: 4,400千円、間接経費: 1,320千円); 2008年度: 5,720千円 (直接経費: 4,400千円、間接経費: 1,320千円); 2007年度: 7,540千円 (直接経費: 5,800千円、間接経費: 1,740千円)
• キーワード: 薬理学 / タンパク質 / 遺伝病 / cystic fibrosis / FAP / CFTR / transthyretin / phosphatidic acid / mucin / 小胞体 / アミロイド / ENaC / 嚢胞性線維症(CF) / 家族性アミロイドポリニューロパチー(FAP) / calnexin(CNX) / transthyretin(TTR) / 小胞体関連分解(ERAD) / BiP / calnexin / toll-like receptor

研究概要

嚢胞性線維症(CF)および家族性アミロイドポリニューロパチー(FAP)の治療薬の開発研究はあまり進展していない。本研究では,約70%のCF患者が有する変異タンパク質ΔF508 CFTRの細胞内品質管理機構を明らかにした。さらに、FAPの原因タンパク質であるtransthyretin(TTR)の細胞内品質管理機構に関する研究により、変異TTR産生抑制薬の新規の概念を提唱し,また、変異TTRの小胞体品質管理にBiPが特異的に関わることも明らかにした

研究成果

• [雑誌論文] Role of the glutamic acid 54 residue in transthyretin stability and thyroxine binding (2010)
  • 著者名/発表者名: Miyata M, Sato T, Mizuguchi M, Nakamura T, Ikemizu S, Nabeshima Y, Susuki S, Suwa Y, Morioka H, Ando Y, Suico MA, Shuto T, Koga T, Yamagata Y, Kai H
  • 雑誌名: Biochemistry 49 ページ: 114-23
  • 査読あり
• [雑誌論文] Heat shock treatment with mild electrical stimulation safely reduced inflammatory markers in healthy male subjects (2010)
  • 著者名/発表者名: Kondo, T., Sasaki, K., Adachi, H., Nakayama, Y., Hatemura, M., Matsuyama, R., Tsuruzoe, K., Furukawa, N., Motoshima, H., Morino, S., Yamashita Y., Miyamura N., Kai H., Araki E
  • 雑誌名: Obesity Research, Clinical Practice 4
  • NAID: 120003184552
  • 査読あり
• [雑誌論文] TLR3 induction by anticancer drugs potentiates poly I:C-induced tumor cell apoptosis (2010)
  • 著者名/発表者名: Manabu Taura, R. Fukuda, Mary Ann Suico, Ayaka Eguma, Tomoaki Koga, Tsuyoshi Shuto, Takashi Sato, Saori Koga Morino, Hirofumi Kai
  • 雑誌名: Cancer Sci (in press)
  • NAID: 10026594490
  • 査読あり
• [雑誌論文] Modified Mild Heat Shock Modality Attenuates Hepatic Ischemia/Reperfusion Injury (2010)
  • 著者名/発表者名: Mariko Oba, Mary Ann Suico, Saori Morino, Shuichiro Yano, Takashi Matsuno, Tomoaki Koga, Takashi Sato, Tsuyoshi Shuto, Hirofumi Kai
  • 雑誌名: J. Surg. Res (in press)
  • 査読あり
• [雑誌論文] Modified Mild Heat Shock Modality Attenuates Hepatic Ischemia/Reperfusion Injury (2010)
  • 著者名/発表者名: Oba M, et al.
  • 雑誌名: J Surg Res. (in press)
  • 査読あり
• [雑誌論文] TLR3 induction by anticancer drugs potentiates poly I : C-induced tumor cell apoptosis (2010)
  • 著者名/発表者名: Taura M, et al.
  • 雑誌名: Cancer Sci. (in press)
  • 査読あり
• [雑誌論文] The endoplasmic reticulum-associated degradation of transthyretin variants is negatively regulated by BiP in mammalian cells (2009)
  • 著者名/発表者名: Susuki S, Sato T, Miyata M, Momohara M, Suico MA, Shuto T, Ando Y, Kai H
  • 雑誌名: J Biol Chem 284 ページ: 8312-8321
  • 査読あり
• [雑誌論文] Calreticulin positively regulates the expression and function of epithelial sodium channel (2009)
  • 著者名/発表者名: Takuya Sugahara, Tomoaki Koga, Keiko Ueno-Shuto, Tsuyoshi Shuto, Eriko Watanabe, Maekawa A., Kitamura K., Tomita K., Ai Mizuno, Takashi Sato, Mary Ann Suico, Hirofumi Kai
  • 雑誌名: Exp. Cell Res 315 ページ: 3294-300
  • 査読あり
• [雑誌論文] A novel combination of mild electrical stimulation and hyperthermia: general concepts and applications (review) (2009)
  • 著者名/発表者名: Hirofumi Kai, Mary Ann Suico, Saori Morino, Tatsuya Kondo, Mariko Oba, Mikiko Noguchi, Tsuyoshi Shuto, Eiichi Araki
  • 雑誌名: Int. J. Hyperthermia 25 ページ: 655-660
  • 査読あり
• [雑誌論文] The expression of antimicrobial peptide lysozyme is increased by treatment with silver nanoparticle (Atomyball SR) in mammalian epithelial cells (2009)
  • 著者名/発表者名: Mary Ann Suico, Atsushi Tanaka, Tsuyoshi Shuto, Hirofumi Kai
  • 雑誌名: J. Health Sci 55 ページ: 456-462
  • 査読あり
• [雑誌論文] The Endoplasmic Reticulum-associated Degradation of Transthyretin Variants Is Negatively Regulated by BiP in Mammalian Cells (2009)
  • 著者名/発表者名: Susuki S, et al.
  • 雑誌名: J Biol Chem. 284(13) ページ: 8312-8321
  • 査読あり
• [雑誌論文] Calreticulin positively regulates the expression and function of epithelial sodium channel (2009)
  • 著者名/発表者名: Sugahara T, et al.
  • 雑誌名: Exp Cell Res. 315(19) ページ: 3294-3300
  • 査読あり
• [雑誌論文] Role of the glutamic acid 54 residue in transthyretin stability and thyroxine binding (2009)
  • 著者名/発表者名: Miyata M, et al.
  • 雑誌名: Biochemistry 49(19) ページ: 114-123
  • 査読あり
• [雑誌論文] A novel combination of mild electrical stimulation and hyperthermia : general concepts and applications (2009)
  • 著者名/発表者名: Kai H, et al.
  • 雑誌名: Int J Hyperthermia 25(8) ページ: 655-660
  • 査読あり
• [雑誌論文] The endoplasmic reticulum -associated degradation of transthyretin variants is negatively regulated by BiP in mammalian cells. (2009)
  • 著者名/発表者名: Susuki S, et al.
  • 雑誌名: J Biol Chem 284(13) ページ: 8312-21
  • 査読あり
• [雑誌論文] Phosphatidic acid metabolism regulate the intracellular trafficking and retrotranslocation of cystic fibrosis transmembrane conductance regulator. Biochem (2008)
  • 著者名/発表者名: Yasuaki Hashimoto, Tsukasa Okiyoneda, Kazutsune Harada, Keiko Ueno, Takuya Sugahara, Atsushi Yamashita, Tsuyoshi Shuto, Mary Ann Suico, Hirofumi Kai
  • 雑誌名: Biochim. Acta (Mol. Cell Res. ) 1783 ページ: 153-162
  • 査読あり
• [雑誌論文] Multi-elemental analysis of serum and amyloid fibrils in familial amyloid polyneuropathy patients (2008)
  • 著者名/発表者名: Susuki S., Ando Y., Sato T., Nishiyama M., Miyata M., Suico MA., Shuto T., Kai H
  • 雑誌名: Amyloid (The Journal of Protein Folding Disorders) 15 ページ: 108-116
  • 査読あり
• [雑誌論文] Interferon-gamma down-regulated Hsp27 and enhances hyperthermia-induced tumor cell death in vitro and tumor suppression in vivo (2008)
  • 著者名/発表者名: Oba M., Yano S., Shuto T., Suico M.A., Eguma A., Kai H
  • 雑誌名: Int. J. Oncol 32 ページ: 1317-1324
  • 査読あり
• [雑誌論文] Role of calnexin in the ER quality control and productive folding of CFTR; differential effect of calnexin knockout on wild-type and DF508 CFTR (2008)
  • 著者名/発表者名: Okiyoneda T., Niibori A., Harada K., Kohno T., Michalak M., Duszyk M., Wada I., Ikawa M., Shuto T., Suico M. A, Kai H
  • 雑誌名: Biochem. Biochim. Acta (Mol. Cell Res. ) 1783 ページ: 1585-94
  • 査読あり
• [雑誌論文] DNA demethylation-dependent enhancement of toll-like receptor-2 gene expression in cystic fibrosis epithelial cells involves SP1-activated transcription (2008)
  • 著者名/発表者名: Takashi Furuta, Tsuyoshi Shuto, Shogo Shimasaki, Yuko Ohira, Mary Ann Suico, Dieter C Gruenert, Hirofumi Kai
  • 雑誌名: BMC Mol Biol 9 ページ: 39-39
  • 査読あり
• [雑誌論文] p53 regulates TLR3 expression and function in human epithelial cell lines (2008)
  • 著者名/発表者名: Manabu Taura, Ayaka Eguma, Mary Ann Suico, Tsuyoshi Shuto, Tomoaki Koga, Kensei Komatsu, Takefumi Komune, Takashi Sato, Hideyuki Saya, Jian-Dong Li, Hirofumi Kai
  • 雑誌名: Mol. Cell. Biol 28 ページ: 6557-67
  • 査読あり
• [雑誌論文] Mild Electrical Stimulation Increases Ubiquitinated Proteins and Hsp72 in A549 Cells via Attenuation of Proteasomal Degredation (2008)
  • 著者名/発表者名: Saori Morino, Mary Ann Suico, Tatsuya Kondo, Erika Sekimoto, Shuichiro Yano. Tomoko Matsuda, Takashi Matsuno, Tsuyoshi Shuto, Eiichi Araki, Hirohumi Kai
  • 雑誌名: J Pharmacol Sci 108 ページ: 222-226
  • 査読あり
• [雑誌論文] Mild Electrical Stimulation with heat shock ameliorates insulin resistance via enhanced insulin signaling. Increases Ubiquitinated Proteins and Hsp72 in A549 Cells via Attenuation of Proteasomal Degradation (2008)
  • 著者名/発表者名: Saori Morino, Tatsuya Kondo, Kazunari Sasaki, Hironori Adachi, Mary Ann Suico, Erika Sekimoto, Tomoko Matsuda, Tsuyoshi Shuto, Eiichi Araki, Hirofumi Kai
  • 雑誌名: PLoS ONE 3(12)
  • 査読あり
• [雑誌論文] Role of calnexin in the ER quality control and productive folding of cftr ; differential effect of calnexin knockout on wild -type and DF508 CFTR. (2008)
  • 著者名/発表者名: Okiyoneda T, et al.
  • 雑誌名: BBA - Molecular Cell Research 1783 ページ: 1585-94
  • 査読あり
• [雑誌論文] Mild Electrical Stimulation with heat shock ameliorates insulin resistance via enhanced insulin signaling. Increases Ubiquitinated Proteins and Hsp72 in A549 Cells via Attenuation of Proteasomal Degredation. (2008)
  • 著者名/発表者名: Morino S, et al.
  • 雑誌名: PLoS ONE 3(12)
  • 査読あり
• [雑誌論文] Multi-elemental analysis of serum and amyloid fibrils in familial amyloid polyneuropathy patients. (2008)
  • 著者名/発表者名: Susuki S, et. al.
  • 雑誌名: Amyloid (The Journal of Protein Folding Disorders) (in press)
  • 査読あり
• [雑誌論文] Interferon-gamma down-regulated Hsp27 and enhances hyperthermia-induced tumor cell death in vitro and tumor suppression in vivo (2008)
  • 著者名/発表者名: Oba M, et. al.
  • 雑誌名: Int.J.Oncol. (in press)
  • 査読あり
• [雑誌論文] Phosphatidic acid metabolism regulate the intracellular trafficking and retrotranslocation of cystic fibrosis transmembrane conductance regulator. (2008)
  • 著者名/発表者名: Yasuaki Hashimoto, et. al.
  • 雑誌名: BBA-Mol Cell Res. 1783(1) ページ: 153-162
  • 査読あり
• [雑誌論文] Curucumin enhances cystic fibrosis transmembrane regulator expression by down-regulating calreticulin, Biochem (2007)
  • 著者名/発表者名: Kazutsune Harada, Tsukasa Okiyoneda, Yasuaki Hashimoto, Kimiko Oyokawa, Kimitoshi Nakamura, Mary Ann Suico, Tsuyoshi Shuto, Hirofumi Kai
  • 雑誌名: Biophys. Res. Commun 353 ページ: 351-356
  • 査読あり
• [雑誌論文] Increased responsiveness to TLR2 and TLR4 ligands during dimethylsulfoxideinduced neutrophil-like differentiation of HL-60 myeloid leukemia cells (2007)
  • 著者名/発表者名: Tsuyoshi Shuto, Takashi Furuta, Judy Cheung, Dieter C. Gruenert, Yuko Ohira, Shogo Shimasaki, Mary Ann Suico, Keizo Sato, Hirofumi Kai
  • 雑誌名: Leuk Res 31 ページ: 1721-8
  • 査読あり
• [雑誌論文] Curucumin enhances cystic fibrosis transmembrane regulator expression by down-regulating calreticuline (2007)
  • 著者名/発表者名: Kazutsune Harada, et. al.
  • 雑誌名: Biochem.Biophys.Res.Commun 353 ページ: 351-356
  • 査読あり
• [雑誌論文] Endoplasmic reticulum quality control regulates the fate of transthyretin variants in the cell. (2007)
  • 著者名/発表者名: Takashi Sato, et. al.
  • 雑誌名: The EMBO Journal. 31(12) ページ: 1721-8
  • 査読あり
• [雑誌論文] Increased responsiveness to TLR2 and TLR4 ligands during dimethylsulfoxide-induced neutrophil-like differentiation of HL-60 myeloid leukemia cells (2007)
  • 著者名/発表者名: Tsuyoshi Shuto, et. al.
  • 雑誌名: Leukemia Research 31(12) ページ: 1721-8
  • 査読あり
• [雑誌論文] Heat shock suppresses human NK cell cytotoxicity via regulation of perforin (2007)
  • 著者名/発表者名: Hideki Harada, et. al.
  • 雑誌名: International Journal Of Hyperthermia 23:8 ページ: 657-665
  • 査読あり
• [雑誌論文] Endoplasmic reticulum quality control regulates the fate of transthyretin variants in the cell
  • 著者名/発表者名: Takashi Sato, Seiko Susuki, Mary Ann Suico, Masanori Miyata, Yukio Ando, Mineyuki Mizuguchi, Makoto Takeuchi, Mizuki Dobashi, Tsuyoshi Shuto, Hirofumi Kai
  • 雑誌名: EMBO J 26 ページ: 2501-2512
  • 査読あり
• [学会発表] HRD1によるABCトランスポーターABCG5/8の翻訳後発現制御 (2010)
  • 著者名/発表者名: 鈴木伸悟, 首藤剛, 新堀晶子, 佐藤卓史, 杉山崇, 高田龍平, 金子雅幸, Mary Ann Suico, 古賀友紹, 森野沙緒里, 鈴木洋史, 甲斐広文
  • 学会等名: 日本薬学会第130回年会
  • 発表場所: 岡山コンベンションセンター
• [学会発表] Combination of heat shock and mild electrical stimulation improves insulin resistance and visceral fat accumulation (2009)
  • 著者名/発表者名: S. Morino
  • 学会等名: The 4th International Congress on Stress Responses in Biology and Medicine
  • 発表場所: Gateaux Kingdom Sapporo Hotel, Spa Resort, Sapporo, Japan
• [学会発表] Endoplasmic reticulum stress increases the expression of toll-like receptor-2 in epithelial cells (2009)
  • 著者名/発表者名: S. Shimasaki
  • 学会等名: Cell Stress Society International 2009
  • 発表場所: Gateaux Kingdom Sapporo Hotel, Spa Resort, Sapporo, Japan
• [学会発表] The endoplasmic reticulum-associated degradation of transthyretin variants is negatively regulated by BiP (2009)
  • 著者名/発表者名: T. Sato
  • 学会等名: Cell Stress Society International 2009
  • 発表場所: Gateaux Kingdom Sapporo Hotel, Spa Resort, Sapporo, Japan
• [学会発表] The endoplasmic reticulum-associated degradation of transthyretin variants is negatively regulated by BiP in mammalian cells (2009)
  • 著者名/発表者名: T. Sato
  • 学会等名: FASEB SUMMER RESEARCH CONFERENCES
  • 発表場所: Vermont Academy, Vermont, USA
• [学会発表] The role of Glu54 in transthyretin for protein stability, thyroxine binding and secretion from the cells (2009)
  • 著者名/発表者名: M. Miyata
  • 学会等名: FASEB SUMMER RESEARCH CONFERENCES
  • 発表場所: Vermont Academy, Vermont, USA
• [学会発表] The endoplasmic reticulum-associated degradation of transthyretin variants is negatively regulated by BiP in mammalian cells (2009)
  • 著者名/発表者名: T.Sato, S.Susuki, M.Miyata, M.Momohara, M.A.Suico, T.Shuto, Y.Ando, H.Kai
  • 学会等名: FASEB SUMMER RESEARCH CONFER ENCES, From unfolded proteins in the endoplasmic reticulum to disease
  • 発表場所: Vermont, USA
• [学会発表] The endoplasmic reticulum-associated degradation of transthyretin variants is negatively regulated by BiP (2009)
  • 著者名/発表者名: T.Sato, S.Susuki, M.Miyata, M.Momohara, Y.Sako, M.A.Suico, T.Shuto, H.Kai
  • 学会等名: Cell Stress Society International 2009
  • 発表場所: Sapporo, Japam
• [学会発表] The role of coat protein complex II machinery on the secretion, endoplasmic reticulum retention and endoplasmic reticulum-associated degradation of transthyretin (2008)
  • 著者名/発表者名: Takashi Sato
  • 学会等名: VIIth International Symposium on Familial Amyloid Polyneuropathy and 1st International Workshop on Hereditary Amy loidosis
  • 発表場所: King's College London イギリス
  • 年月日: 2008-09-04
• [学会発表] The endoplasmic reticulm retention and degradation of transthyretin are regulated by the molecular chaperone BiP in mammalian cells (2008)
  • 著者名/発表者名: Seiko Susuki
  • 学会等名: VIIth International Sy mposium on Familial Amyloid Polyneuropathy and Ist International Workshop on Hereditary Amyloidosis
  • 発表場所: King' s College London イギリス
  • 年月日: 2008-09-04
• [学会発表] Glu54 mutations in transthyretin affect thyroxine binding and tetramer stability, resu lting in aggressive familial amyloid polyneuropathy (2008)
  • 著者名/発表者名: Masanori Miyata
  • 学会等名: VIIth International Symposium on Familial Amyloid Polyneuropathy and Ist International Workshop on Hereditary Amyloidosis
  • 発表場所: King' S College London イギリス
  • 年月日: 2008-09-04
• [学会発表] p53 Regulates TLR3 Expression and Function in Human Epthelial Cell Lines (2008)
  • 著者名/発表者名: A. Eguma
  • 学会等名: The American Society for Cell Biology 48th Annual Meeting
  • 発表場所: Moscon convention center, San Francisco, USA
• [学会発表] Curcumin Inhibits Peptidoglycan-Mediated Inflammatory Response in Human Cystic Fibrosis Bronchial Epithelial Cells through Inhibition of TLR2 Gene (2008)
  • 著者名/発表者名: Y. Ohira
  • 学会等名: The 22nd Annual North American Cystic Fibrosis Conference
  • 発表場所: Orland, Florida, USA
• [学会発表] ER RETENTION OF CFTR IS CRUCIAL FOR SP1-DEPENDENT UP-REGULATION OF TLR2 EXPRESSION INΔF508-CFTR-EXPRESSING CF BRONCHIAL EPITHELIAL CELLS (2008)
  • 著者名/発表者名: S. Shimasaki
  • 学会等名: The 22nd Annual North American Cystic Fibrosis Conference
  • 発表場所: Orland, Florida, USA
• [学会発表] The endoplasmic reticulm retention and degradation of transthyretin are regulated by the molecular chaperone BiP in mammalian cells (2008)
  • 著者名/発表者名: S. Susuki
  • 学会等名: VIIth International Symposium on Familial Amyloid Polyneuropathy and Ist International Workshop on Hereditary Amyloidosis
  • 発表場所: King's College London, London, UK
• [学会発表] The role of coat protein complex II machinery on the secretion, endoplasmic reticulum retention and endoplasmic reticulum-associated degradation of transthyretin (2008)
  • 著者名/発表者名: T. Sato
  • 学会等名: VIIth International Symposium on Familial Amyloid Polyneuropathy and Ist International Workshop on Hereditary Amyloidosis
  • 発表場所: King's College London, London, UK
• [学会発表] Glu54 mutations in transthyretin affect thyroxine binding and tetramer stability, resulting in aggressive familial amyloid polyneuropathy (2008)
  • 著者名/発表者名: M. Miyata
  • 学会等名: VIIth International Symposium on Familial Amyloid Polyneuropathy and Ist International Workshop on Hereditary Amyloidosis
  • 発表場所: King's College London, London, UK
• [学会発表] The Expression of Myelid-1-like Factor (MEF/Elf4),an ETS Transcription Factor,Is Modulated by p53. (2007)
  • 著者名/発表者名: M.Taura, et. al.
  • 学会等名: The American Society for Cell Biology 47th Annual Meeting
  • 発表場所: Washington,DC.,USA
  • 年月日: 2007-12-03
• [学会発表] Phosphatidic Acid Metabolism Regulates the Intracellular Trafficking of CFTR (2007)
  • 著者名/発表者名: S. Mizunoe
  • 学会等名: The American Society for Cell Biology 47th Annual Meeting
  • 発表場所: Washington Convention Center, Washington, DC., USA
• [学会発表] The Expression of Myelid-1-like Factor (MEF/Elf4), an ETS Transcription Factor, Is Modulated by p53 (2007)
  • 著者名/発表者名: M. Taura
  • 学会等名: The American Society for Cell Biology 47th Annual Meeting
  • 発表場所: Washington Convention Center, Washington, DC., USA
• [学会発表] Investigation of the Mechanism of Severe Familial Amyloidotic Polyneurophaty (2007)
  • 著者名/発表者名: M. Miyata
  • 学会等名: The American Society for Cell Biology 47th Annual Meeting
  • 発表場所: Washington Convention Center, Washington, DC., USA
• [学会発表] Interferon-gamma Enhances the Induction of Cell Death by Heat-shock and Cisplatin through Hsp27 Down-Regulation (2007)
  • 著者名/発表者名: M. Oba
  • 学会等名: The American Society for Cell Biology 47th Annual Meeting
  • 発表場所: Washington Convention Center, Washington, DC., USA
• [備考]
  • URL: http://www.molmed730.org/
• [備考]
  • URL: http://molmed730.org/
• [備考]
  • URL: http://molmed730.org/