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Drug discovery for Familial amyloid polyneuropathy (FAP), an incurable hereditary disease

Research Project

Project/Area Number 25253012
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Pharmacology in pharmacy
Research InstitutionKumamoto University

Principal Investigator

KAI HIROFUMI  熊本大学, 大学院生命科学研究部, 教授 (30194658)

Co-Investigator(Kenkyū-buntansha) SHUTO Tsuyoshi  熊本大学, 大学院生命科学研究部(薬学系), 准教授 (80333524)
SUICO Mary Ann Soten  熊本大学, 大学院生命科学研究部(薬学系), 助教 (20363525)
Project Period (FY) 2013-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥47,450,000 (Direct Cost: ¥36,500,000、Indirect Cost: ¥10,950,000)
Fiscal Year 2015: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
Fiscal Year 2014: ¥8,970,000 (Direct Cost: ¥6,900,000、Indirect Cost: ¥2,070,000)
Fiscal Year 2013: ¥29,510,000 (Direct Cost: ¥22,700,000、Indirect Cost: ¥6,810,000)
Keywords化合物ライブラリースクリーニング / 家族性アミロイドポリニューロパチー / アミロイドーシス / トランスサイレチン
Outline of Final Research Achievements

Familial amyloid polyneuropathy (FAP) is one of the hereditary amyloidoses caused by a point mutation in the human plasma protein, transthyretin (TTR). Amyloid fibrils derived from TTR variants accumulate in peripheral nerves and visceral organs, leading to inflammation-associated failure of multiple organs. TTR variants are easily dissociated from tetramer to monomer, which is the first step to amyloidosis, due to the low energetic stability of TTR variant tetrameric structure in comparison with wild-type (WT) TTR. We aimed to determine novel drugs that could either stabilize extracellular TTR tetramer or inhibit TTR secretion from the cells by high-throughput screening (HTS). Here, Western blotting- and Thioflavin-based biochemical assays identified thirteen compounds that stabilize the TTR tetramer as well as two TTR amyloid-solubilizing agents, and one inhibitor of TTR secretion from the cells were identified in this study.

Report

(4 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • Research Products

    (30 results)

All 2016 2015 2014 2013 Other

All Journal Article (11 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 11 results,  Open Access: 8 results,  Acknowledgement Compliant: 1 results) Presentation (17 results) (of which Int'l Joint Research: 5 results) Remarks (2 results)

  • [Journal Article] TALENs Facilitate Single-step Seamless SDF Correction of F508del CFTR in Airway Epithelial Submucosal Gland Cell-derived CF-iPSCs.2016

    • Author(s)
      Suzuki S, Sargent RG, Illek B, Fischer H, Esmaeili-Shandiz A, Yezzi MJ, Lee A, Yang Y, Kim S, Renz P, Qi Z, Yu J, Muench MO, Beyer AI, Guimaraes AO, Ye L, Chang J, Fine EJ, Cradick TJ, Bao G, Rahdar M, Porteus MH, Shuto T, Kai H, Kan YW, Gruenert DC
    • Journal Title

      Molecular Therapy Nucleic Acids

      Volume: 5 Pages: e273-e273

    • DOI

      10.1038/mtna.2015.43

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The effect of mild electrical stimulation with heat shock on diabetic KKAy mice.2015

    • Author(s)
      Kai Y, Tsurekawa Y, Fukuda R, Omachi K, Piruzyan M, Okamoto Y, Motomura K, Suico MA, Shuto T, Kondo T, Araki E, Kai H.
    • Journal Title

      Integr Mol Med.

      Volume: 3 Issue: 1 Pages: 473-477

    • DOI

      10.15761/imm.1000190

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Structural stabilization of transthyretin by a new compound, 6-benzoyl-2-hydroxy-1H-benzo[de]isoquinoline-1,3(2H)-dione2015

    • Author(s)
      Yokoyama T, Takaki S, Chosa K, Sato T, Suico MA, Teranishi Y, Shuto T, Mizuguchi M, Kai H
    • Journal Title

      J Pharmacol Sci.

      Volume: 129 Issue: 4 Pages: 240-243

    • DOI

      10.1016/j.jphs.2015.09.006

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 細胞内ストレスと生活習慣病-分子シャペロンHsp72の耐糖能改善効果とその機序-2015

    • Author(s)
      荒木 栄一, 近藤 龍也, 甲斐 広文
    • Journal Title

      日本体質医学会雑誌

      Volume: 77 Pages: 163-166

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Endoplasmic Reticulum (ER) Stress Induces Sirtuin 1 (SIRT1) Expression via the PI3K-Akt-GSK3β Signaling Pathway and Promotes Hepatocellular Injury.2015

    • Author(s)
      Koga T, Suico MA, Shimasaki S, Watanabe E, Kai Y, Koyama K, Omachi K, Morino-Koga S, Sato T, Shuto T, Mori K, Hino S, Nakao M, Kai H.
    • Journal Title

      J Biol Chem.

      Volume: 290 Issue: 51 Pages: 30366-30374

    • DOI

      10.1074/jbc.m115.664169

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Preemptive quality control protects the ER from protein overload via the proximity of ERAD components and SRP.2015

    • Author(s)
      Kadowaki H, Nagai A, Maruyama T, Takami Y, Satrimafitrah P, Kato H, Honda A, Hatta T, Natsume T, Sato T, Kai H, Ichijo H, Nishitoh H
    • Journal Title

      Cell reports

      Volume: 13 Issue: 5 Pages: 944-956

    • DOI

      10.1016/j.celrep.2015.09.047

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Cross-talk between PKA-Cβ and p65 mediates synergistic induction of PDE4B by roflumilast and NTHi.2015

    • Author(s)
      Susuki-Miyata S, Miyata M, Lee BC, Xu H, Kai H, Yan C, Li JD.
    • Journal Title

      Proc Natl Acad Sci U S A.

      Volume: 112 Issue: 14

    • DOI

      10.1073/pnas.1418716112

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Inhibition of post-translational N-glycosylation by HRD1 that controls the fate of ABCG5/8 transporter.2014

    • Author(s)
      Suzuki S, Shuto T, Sato T, Kaneko M, Takada T, Suico MA, Cyr DM, Suzuki H, Kai H
    • Journal Title

      Scientific reports

      Volume: 4 Issue: 1 Pages: 4258-4258

    • DOI

      10.1038/srep04258

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Evaluation of Three-Dimensional Cultured HepG2 Cells in a Nano Culture Plate System: an In Vitro Human Model of Acetaminophen Hepatotoxicity.2013

    • Author(s)
      Kohei Aritomi, Yoichi Ishitsuka, Yoshiro Tomishima, Daisuke Shimizu, Nazuki Abe, Tsuyoshi Shuto, Mitsuru Irikura, Hirofumi Kai, and Tetsumi Irie.
    • Journal Title

      J Pharmacpl Sci.

      Volume: 124 Pages: 218-229

    • NAID

      130003391476

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Inhibition of PDE4B suppresses inflammation by increasing expression of the deubiquitinase CYLD2013

    • Author(s)
      Komatsu K
    • Journal Title

      Nature Communications

      Volume: 4 Issue: 1 Pages: 1684-1684

    • DOI

      10.1038/ncomms2674

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Mild electrical stimulation at 0.1-ms pulse width induces p53 protein phosphorylation and G2 arrest in human epithelial cells.2013

    • Author(s)
      Fukuda ft, Suico MA, Koyama K, Omachi K, Kai Y, Matsuyama S, Mitsutake K, Taura M, Mo rino-Koga S, Shuto T, Kai H.
    • Journal Title

      Journal of Biological Chemistry

      Volume: 288(22) Issue: 22 Pages: 16117-16126

    • DOI

      10.1074/jbc.m112.442442

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Presentation] 遺伝性疾患患者由来iPS細胞を用いた遺伝子治療と再生医療;遺伝性呼吸器疾患嚢胞性繊維症(Cystic Fibrosis, CF)患者由来iPS細胞のゲノム修復及び機能的気道上皮細胞への分化誘導2016

    • Author(s)
      鈴木 伸悟、R. Geoffrey Sargent、帖佐 圭佑、Beate Illek、Horst Fischer、Alaleh Eamaeili-Shandiz、首藤 剛、甲斐 広文、Yuet. W Kan、Dieter.C Gruenert
    • Organizer
      第89回日本薬理学会年会
    • Place of Presentation
      パシフィコ横浜(神奈川)
    • Year and Date
      2016-03-09
    • Related Report
      2015 Annual Research Report
  • [Presentation] Molecular mechanism of the intracellular quality control of TTR by Hsp472015

    • Author(s)
      Y. Wakita, R. Yamakawa, K. Chosa, S. Takaki, Y. Teranishi, T. Sato, M.Suico, T. Shuto, H. Kai
    • Organizer
      2015 cell biology ascb annual meeting
    • Place of Presentation
      San Diego(USA)
    • Year and Date
      2015-12-12
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Hsp47によるTTRタンパク質の細胞内品質管理機構の解明2015

    • Author(s)
      脇田 有梨子、山川 瑠斐子、帖佐 圭佑、高木 舜、寺西 ゆり子、佐藤 卓史、Mary Ann Suico、首藤 剛、甲斐 広文
    • Organizer
      BMB2015
    • Place of Presentation
      神戸ポートアイランド(兵庫)
    • Year and Date
      2015-12-01
    • Related Report
      2015 Annual Research Report
  • [Presentation] Hsp47によるTTRタンパク質の細胞内品質管理機構の解明2015

    • Author(s)
      脇田 有梨子、山川 瑠斐子、帖佐 圭佑、高木 舜、寺西 ゆり子、佐藤 卓史、Mary Ann Suico、首藤 剛、甲斐 広文
    • Organizer
      第32回日本薬学会九州支部大会
    • Place of Presentation
      九州保健福祉大学(宮崎)
    • Year and Date
      2015-11-28
    • Related Report
      2015 Annual Research Report
  • [Presentation] バーチャルスクリーニングシステムを活用した、家族性アミロイドポリニューロパチー原因タンパク質 TTR の四量体安定化剤の同定2015

    • Author(s)
      高木 舜、帖佐 圭佑、横山 武司、佐藤 卓史、Mary Ann Suico、寺西 ゆり子、首藤 剛、水口 峰之、甲斐 広文
    • Organizer
      第37回生体膜と薬物の相互作用シンポジウム2015
    • Place of Presentation
      熊本大学薬学部(熊本)
    • Year and Date
      2015-11-19
    • Related Report
      2015 Annual Research Report
  • [Presentation] Hsp47によるTTRタンパク質の細胞内品質管理機構の解明2015

    • Author(s)
      脇田 有梨子、山川 瑠斐子、帖佐 圭佑、高木 舜、寺西 ゆり子、佐藤 卓史、Mary Ann Suico、首藤 剛、甲斐 広文
    • Organizer
      第37回生体膜と薬物の相互作用シンポジウム2015
    • Place of Presentation
      熊本大学薬学部(熊本)
    • Year and Date
      2015-11-19
    • Related Report
      2015 Annual Research Report
  • [Presentation] 6-benzoyl-2-hydroxy-1H-benzo[de]isoquin oline-1,3(2H)-dione is a novel transthyretin stabilizer for familial amyloid polyneuropathy2015

    • Author(s)
      S. Takaki, K. Chosa, T. Yokoyama, Y. Teranishi, Y. Wakita, T. Sato, M. Suico, T. Shuto, M. Mizuguchi, H. Kai
    • Organizer
      International Symposium on Chronic Inflammatory Diseases, Kumamoto (ISCIDK2015)
    • Place of Presentation
      熊本大学(熊本)
    • Year and Date
      2015-10-16
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] High throughput screening-based identification of transthyretin stabilizers for familial amyloid polyneuropathy2015

    • Author(s)
      Y. Teranishi, K. Chosa, T. Shuto, S. Takaki, Y. Wakita, T. Sato, M. Suico, T. Yamashita, H. Kai
    • Organizer
      International Symposium on Chronic Inflammatory Diseases, Kumamoto (ISCIDK2015)
    • Place of Presentation
      熊本大学(熊本)
    • Year and Date
      2015-10-16
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The molecular quality control of TTR by Hsp472015

    • Author(s)
      Y. Wakita, R. Yamakawa, K. Chosa, S. Takaki, Y. Teranishi, T. Sato, S. Ann, T. Shuto, H. Kai
    • Organizer
      International Symposium on Chronic Inflammatory Diseases, Kumamoto (ISCIDK2015)
    • Place of Presentation
      熊本大学(熊本)
    • Year and Date
      2015-10-16
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 遺伝性腎炎Alport症候群の病態進行抑制因子および原因タンパク質に焦点を当てた新規治療薬の開発2015

    • Author(s)
      大町 紘平, 福田 亮介, 嘉村 美里, 寺本 啓祐, 横田 翼, 本村 敬士, 山川 瑠斐子, Mary Ann Suico, 首藤 剛, 甲斐 広文
    • Organizer
      第6回分子腎臓フォーラム
    • Place of Presentation
      グランフロント大阪(大阪)
    • Year and Date
      2015-09-05
    • Related Report
      2015 Annual Research Report
  • [Presentation] Characterization of the intracellular behavior of COL4A5 and clarification of molecular mechanism of alport syndrome2015

    • Author(s)
      K. Omachi, M. Kamura, K. Teramoto, R. Fukuda, M. Suico, T. Shuto, H. Kai
    • Organizer
      52nd ERA-EDTA CONGRESS LONDON 2015
    • Place of Presentation
      London(UK)
    • Year and Date
      2015-05-28
    • Related Report
      2015 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Screening of small compounds to develop endoplasmic reticulum-oriented drug for familial amyloid polyneuropathy.2014

    • Author(s)
      K. Chosa, S. Takaki, R. Yamakawa, Y. Wakita, Y. Teranishi, T. Sato, T. Yokoyama, M. Mizuguchi, M. Suico, T. Shuto, H. Kai
    • Organizer
      The 2014 ascb/ifcb Meeting
    • Place of Presentation
      Philadelphia(USA)
    • Year and Date
      2014-12-06 – 2014-12-10
    • Related Report
      2014 Annual Research Report
  • [Presentation] 小胞体品質管理機構を標的とした家族性アミロイドポリニューロパチー(FAP)の新規治療薬開発2014

    • Author(s)
      帖佐 圭佑, 高木 舜, 山川 瑠斐子, 脇田 有梨子, 寺西 ゆり子, 佐藤 卓史, 横山 武司, 水口 峰之, Mary Ann Suico , 首藤 剛, 甲斐 広文
    • Organizer
      第37回日本分子生物学会年会
    • Place of Presentation
      パシフィコ横浜(神奈川県横浜市)
    • Year and Date
      2014-11-25 – 2014-11-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] バーチャルおよびハイスループットスクリーニングを用いた家族性アミロイドポリニューロパチーの新規治療薬の開発2014

    • Author(s)
      帖佐 圭佑, 高木 舜, 脇田 有梨子, 寺西 ゆり子, 山川 瑠斐子, 佐藤 卓史, 横山 武司, 水口 峰之, Mary Ann Suico , 首藤 剛, 甲斐 広文
    • Organizer
      第8回次世代を担う若手医療薬科学シンポジウム
    • Place of Presentation
      熊本大学薬学部(熊本県熊本市)
    • Year and Date
      2014-11-15 – 2014-11-16
    • Related Report
      2014 Annual Research Report
  • [Presentation] The endoplasmic reticulum-oriented drug development for familial amyloid polyneuropathy2014

    • Author(s)
      K. Chosa, R. Yamakawa, T. Sato, T. Yokoyama, M. Mizuguchi, M. Suico, T. Shuto, H. Kai
    • Organizer
      WCP2014 17th World Congress of Basic & Clinical Pharmacology
    • Place of Presentation
      Cape Town(South Africa)
    • Year and Date
      2014-07-13 – 2014-07-18
    • Related Report
      2014 Annual Research Report
  • [Presentation] The endoplasmic reticulum-oriented drug development for familial amyloid polyneuropathy2013

    • Author(s)
      K. Chosa, R. Yamakawa, T. Sato, T. Yokoyama, M. Mizuguchi, M. Suico, T. Shuto, H. Kai
    • Organizer
      2013 ASCB Annual Meeting
    • Place of Presentation
      The New Orleans Ernest N. Morial Convention Center, New Orleans, Lousiana,USA
    • Related Report
      2013 Annual Research Report
  • [Presentation] The endoplasmic reticulum-oriented drug development for transthyretin familial amyloid polyneuropathy2013

    • Author(s)
      Keisuke Chosa , Ruiko Yamakawa , Takashi Sato , Takeshi Yokoyama , Mineyuki Mizuguchi , Mary Ann Suico ,Tsuyoshi Shuto , Hirofumi Kai
    • Organizer
      IXth International Symposium on Familial Amyloidotic Polyneuropathy
    • Place of Presentation
      Auditorio do Centro de Convencoes Antonio Seabra Moggi,Rio de Janeiro, Brazil
    • Related Report
      2013 Annual Research Report
  • [Remarks] 熊本大学大学院薬学教育部  遺伝子機能応用学研究室

    • URL

      http://molmed730.org/index.html

    • Related Report
      2015 Annual Research Report
  • [Remarks] 熊本大学大学院薬学教育部 遺伝子機能応用学研究室

    • URL

      http://molmed730.org/index.html

    • Related Report
      2013 Annual Research Report

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Published: 2013-05-15   Modified: 2019-07-29  

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