Seeking for target proteins of autophagy related small chemical compounds

• Project/Area Number: 15K19000
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General medical chemistry
• Research Institution: Tohoku University
• Principal Investigator: KIMURA Tomohiro 東北大学, 加齢医学研究所, 助教 (90431501)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 低分子化合物の標的蛋白質

Outline of Final Research Achievements

This study object is to determine target molecules of autophagy related small chemical compounds, such as chloroquine and metformin, and to elucidate the relationships between functions of the molecules and effects of the compounds. TOF-MS analysis revealed the metformin binding protein (MBP) was HMGB1. Metformin inhibited proinflammatory effect of HMGB1 in vitro and in vivo. Furthermore, metformin ameliorated liver injury induced by acetaminophen, as same as anti-HMGB1 antibody. This study elucidated one of an anti-inflammatory target molecule of metformin.

Research Products

• [Journal Article] Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity. (2017)
  • Author(s): Horiuchi T, Sakata N, Narumi Y, Kimura T, Hayashi T, Nagano K, Liu K, Nishibori M, Tsukita S, Yamada T, Katagiri H, Shirakawa R, Horiuchi H.
  • Journal Title: J Biol Chem Volume: 印刷中 Pages: 8436-8446
  • DOI: 10.1074/jbc.m116.769380
  • NAID: 120006331939
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Prostaglandin E2 inhibits neutrophil extracellular trap formation through production of cyclic AMP. (2016)
  • Author(s): 3.K. Shishikura, T. Horiuchi, N. Sakata, D-A Trinh, R. Shirakawa, T. Kimura, Y. Asada, H. Horiuchi*
  • Journal Title: British Journal of Pharmacology Volume: 173 Pages: 319-331
  • DOI: 10.1111/bph.13373
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Secretin receptor involvement in prion-infected cells and animals (2015)
  • Author(s): Kimura T, Nishizawa K, Oguma A., Nishimura Y, Sakasegawa Y, Teruya K, Nishijima I, Doh-ura K.
  • Journal Title: FEBS Lett. Volume: 589 Pages: 2011-2018
  • DOI: 10.1016/j.febslet.2015.05.039
  • Peer Reviewed / Open Access
• [Presentation] Prostaglandin E2 inhibits neutrophil extracellular traps formation through production of cyclic AMP (2015)
  • Author(s): 木村朋寛・宍倉匡祐・堀内嵩弘・坂田菜摘・Trinh Duc-Anh・白川龍太郎・堀内久徳
  • Organizer: 日本分子生物学会・日本生化学会合同大会
  • Place of Presentation: 神戸国際会議場（兵庫県神戸市）
  • Year and Date: 2015-12-02