Development of inflammatory bowel disease treatment by restoration of intestinal epithelial barrier functions

• Project/Area Number: 26860078
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Drug development chemistry
• Research Institution: Osaka University
• Principal Investigator: Akihiro Watari 大阪大学, 薬学研究科(研究院), 助教 (80452465)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 上皮バリア機能制御 / 炎症性腸疾患治療法 / クローディン発現 / タイトジャンクション / 炎症性腸疾患 / クローディン / 上皮バリア / daunorubicin / rebeccamycin

Outline of Final Research Achievements

In this study, we identified daunorubicin and rebecamycin as novel claudin modulators, which can enhance tight junction (TJ) barrier function in intestinal cells. Daunorubicin and rebeccamycin stimulate ATM and ATR kinases in the nucleus, resulting in activation of the downstream molecule, Chk1. Activated Chk1 increases claudin-5 expression, and the product of claudin-5 transitions to TJ following enhanced TJ-barrier. Furthermore, we constituted claudin-2 reporter system, and identified novel claudin-2 modulators from chemical library. In the future, we will investigate therapeutic effect of multiple claudin modulators for an inflammatory bowel disease.

Research Products

• [Journal Article] Checkpoint Kinase 1 Activation Enhances Intestinal Epithelial Barrier Function via Regulation of Claudin-5 Expression (2016)
  • Author(s): Watari A., Hasegawa M., Yagi K., Kondoh M.
  • Journal Title: PLoS One Volume: 11 (1) Issue: 1 Pages: e0145631-e0145631
  • DOI: 10.1371/journal.pone.0145631
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Claudin-1 Binder Enhances Epidermal Permeability in a Human Keratinocyte Model (2015)
  • Author(s): Nakajima M, Nagase S, Iida M, Takeda S, Yamashita M, Watari A, Shirasago Y, Fukasawa M, Takeda H, Sawasaki T, Yagi K, Kondoh M
  • Journal Title: J Pharmacol Exp Ther Volume: 354 Issue: 3 Pages: 440-447
  • DOI: 10.1124/jpet.115.225391
  • Peer Reviewed
• [Journal Article] Anti-HCV effect of mycelia solid culture extracts of Lentinula edodes and low-molecular-weight lignin (2015)
  • Author(s): Matsuhisa K., Yamane S., Okamoto T., Watari A., Kondoh M., Matsuura Y., Yagi K.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 462(1) Issue: 1 Pages: 52-7
  • DOI: 10.1016/j.bbrc.2015.04.104
  • Peer Reviewed
• [Journal Article] C-terminal Clostridium perfringens enterotoxin-mediated antigen delivery for nasal pneumococcal vaccine (2015)
  • Author(s): H. Suzuki, A. Watari, E. Hashimoto, M. Yonemitsu, H. Kiyono, K. Yagi, M. Kondoh, and J. Kunisawa
  • Journal Title: PLoS ONE Volume: 10 Issue: 5 Pages: e0126352-e0126352
  • DOI: 10.1371/journal.pone.0126352
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Use of cell-based screening to identify small-molecule compounds that modulate claudin-4 expression (2015)
  • Author(s): Watari A., Hashegawa M., Muangman T., Yagi K., Kondoh M.
  • Journal Title: Biotechnology Letters Volume: 37(6) Issue: 6 Pages: 1177-85
  • DOI: 10.1007/s10529-015-1791-7
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Discovery of anti-claudin-1 antibodies as candidate therapeutics against hepatitis C virus (2015)
  • Author(s): Mayo Yamashita, Manami Iida, Minoru Tada, Yohitaka Shirasago, Masayoshi Fukasawa, Shotaro Nagase, Akihiro Watari, Akiko Ishii-Watabe, Kiyohito Yagi, Masuo Kondoh
  • Journal Title: J Pharmacol Exp Ther Volume: 353 Issue: 1 Pages: 112-118
  • DOI: 10.1124/jpet.114.217653
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Homoharringtonine increases intestinal epithelial permeability by modulating specific claudin isoforms in Caco-2 cell monolayers (2015)
  • Author(s): Akihiro Watari, Maki Hasegawa, Kiyohito Yagi, Masuo Kondoh
  • Journal Title: Eur J Pharm Biopharm Volume: 89 Pages: 232-238
  • DOI: 10.1016/j.ejpb.2014.12.012
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Development of an anti-claudin-3 and -4 bispecific monoclonal antibody for cancer diagnosis and therapy (2014)
  • Author(s): Xiangru Li, Manami Iida, Minoru Tada, Akihiro Watari, Yumi Kawahigashi, Yuka Kimura, Taku Yamashita, Akiko Ishii-Watabe, Tadayuki Uno, Masayoshi Fukasawa, Hiroki Kuniyasu, Kiyohito Yagi, Masuo Kondoh
  • Journal Title: J Pharmacol Exp Ther Volume: 351 Issue: 1 Pages: 206-213
  • DOI: 10.1124/jpet.114.216911
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Tight junction binderによる核酸医薬の経口投与法開発に関する基盤研究 (2016)
  • Author(s): 渡利彰浩、藤原果奈、渡辺知恵、仁科一隆、永田哲也、近藤昌夫、横田隆徳、村上正裕、八木清仁
  • Organizer: 日本薬学会 第136年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-26
• [Presentation] Tricellular tight junctionを標的とした新規バリア制御技術、angubindin-1の開発 (2016)
  • Author(s): 山本浩樹、井口大輔、早石知浩、Susanne M. Krug、Michael Fromm、渡利彰浩、岡田欣晃、竹田浩之、永浜政博、土井健史、澤崎達也、近藤昌夫、八木清仁
  • Organizer: 日本薬学会 第136年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-26
• [Presentation] Tight junction binderによる上皮バリア制御時における遺伝子発現変動の解析 (2016)
  • Author(s): 関昌孝、井口大輔、早石知浩、吉田有裕美、渡利彰浩、近藤昌夫、八木清仁
  • Organizer: 日本薬学会 第136年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-26
• [Presentation] Claudinを標的とした創薬基盤技術の開発～claudin-4を標的としたがん治療戦略の有効性及び安全性の評価～ (2016)
  • Author(s): 松田基、橋本洋佑、川東祐美、畑智幸、渡利彰浩、近藤昌夫、岡田欣晃、土井健史、八木清仁、多田稔、石井明子、深澤征義
  • Organizer: 日本薬学会 第136年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-26
• [Presentation] Safety profile and anti-tumor activity of a new generated human/mouse cross-reactive Anti-claudin-4 monoclonal antibody in mice (2015)
  • Author(s): Y. Hashimoto, Y. Kawahigashi, T. Hata, Y. Kimura, A. Watari, M. Kondoh, K. Yagi
  • Organizer: European Cancer Congress 2015
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2015-09-25
  • Int'l Joint Research
• [Presentation] Tricellular tight junction binder,angubindin-1の創製とバリア制御活性解析 (2015)
  • Author(s): 井口大輔、早石知浩、Susanne M. Krug、竹田浩之、Michael Fromm、渡利彰浩、澤崎達也、八木清仁、近藤昌夫
  • Organizer: 第31回日本DDS学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-07-02
• [Presentation] Claudin-1を標的とした経皮吸収促進の可能性 (2015)
  • Author(s): 中嶋美咲、山下真代、渡利彰浩、深澤征義、八木清仁、近藤昌夫
  • Organizer: 第31回日本DDS学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-07-02
• [Presentation] Anti-human claudin-1 monoclonal antbodies as anti-Hepatitis C Virus agents. (2014)
  • Author(s): M. Iida, M. Yamashita, S. Nagase, M. Tada, Y. Shirasago, M. Fukasawa, A. Watari, A. Ishii-Watabe, K. Yagi, M. Kondoh
  • Organizer: Antibody Engineering & Therapeutics 2014
  • Place of Presentation: Huntington Beach, CA, U.S.A.
  • Year and Date: 2014-12-07 – 2014-12-11
• [Presentation] Epitope mapping of an anti-claudin-1 monoclonal antibody and its application to preclinical drug discovery. (2014)
  • Author(s): T. Hata, S. Nagase, Y. Shirasago, M. Fukasawa, A. Watari, K. Yagi, M. Kondoh
  • Organizer: Antibody Engineering & Therapeutics 2014
  • Place of Presentation: Huntington Beach, CA, U.S.A.
  • Year and Date: 2014-12-07 – 2014-12-11
• [Presentation] Development of a Novel Bispecific Anti-Claudin Antibody and its Anti-Tumor Activity (2014)
  • Author(s): Y. Kimura, X. Li, M. Iida, M. Tada, A. Watabe-Ishii, M. Fukasawa, Y. Kawahigashi, A. Watari, K. Yagi, M. Kondoh
  • Organizer: Antibody Engineering & Therapeutics 2014
  • Place of Presentation: Huntington Beach, CA, U.S.A.
  • Year and Date: 2014-12-07 – 2014-12-11
• [Presentation] Development of an angulin binder and its tricellular tight junction-modulating activity (2014)
  • Author(s): D. Iguchi, S. M. Krug, T. Hayaishi, A. Watari, M. Nagahama, M. Flomm, K. Yagi, M. Kondoh
  • Organizer: The 2014 ASCB / IFCB meeting
  • Place of Presentation: Pennsylvania, U.S.A.
  • Year and Date: 2014-12-06 – 2014-12-10
• [Presentation] DNA damageが誘導する腸管上皮バリアの機能亢進 (2014)
  • Author(s): 渡利 彰浩、長谷川 真希、八木 清仁、近藤 昌夫
  • Organizer: 37回日本分子生物学会年会
  • Place of Presentation: 神奈川県、横浜市
  • Year and Date: 2014-11-25 – 2014-11-27
• [Presentation] Development of a novel strategy for the enhancement of drug absorption tarageting Claudin (2014)
  • Author(s): M. Iida, H. Suzuki, X. Li, A. Watari, M. Kondoh, and K. Yagi
  • Organizer: 第12回 プロテイン・アイランド 松山国際学術シンポジウム
  • Place of Presentation: 愛媛県、松山市
  • Year and Date: 2014-09-17