Elucidation of the new control mechanism of aging through PAI-1

• Project/Area Number: 17K19881
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Health science and related fields
• Research Institution: Tohoku University
• Principal Investigator: Dan Takashi 東北大学, 医学系研究科, 准教授 (00512451)
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: 老化制御 / PAI-1 / TNFα / LPS / SASP / 老化 / マクロファージ / TGFβ / 転写制御 / SASP(細胞老化関連分泌形質) / TGF-β1 / 発現制御

Outline of Final Research Achievements

As a result of examining the influence of PAI-1 on the transcription of TNFα of SASP (cellular senescence related secretory trait), the new physiological action of PAI-1 which has not been reported so far has been reported that PAI-1 directly enhances macrophage cytokine expression I found it. This action is completely different from conventionally known fibrinolytic control.

Academic Significance and Societal Importance of the Research Achievements

化合物（仮称CompoundX）がPAI-1で誘導されるTNFα産生を抑制することの発見は、新薬創製のシーズとなり、新しい機序の抗炎症剤や抗がん剤の研究開発につながる。

Research Products

• [Journal Article] Identification of novel plasminogen activator inhibitor-1 inhibitors with improved oral bioavailability: Structure optimization of N-acylanthranilic acid derivatives (2018)
  • Author(s): Yamaoka Nagahisa、Murano Kenji、Kodama Hidehiko、Maeda Akihisa、Dan Takashi、Nakabayashi Tetsuo、Miyata Toshio、Meguro Kanji
  • Journal Title: Bioorganic & Medicinal Chemistry Letters Volume: 28 Issue: 4 Pages: 809-813
  • DOI: 10.1016/j.bmcl.2017.11.016
• [Journal Article] Furan- and Thiophene-2-Carbonyl Amino Acid Derivatives Activate Hypoxia-Inducible Factor via Inhibition of Factor Inhibiting Hypoxia-Inducible Factor-1 (2018)
  • Author(s): Kawaguchi Shin-Ichi, Gonda Yuhei, Yamamoto Takuya, Sato Yuki, Shinohara Hiroyuki, Kobiki Yohsuke, Ichimura Atsuhiko, Dan Takashi, Sonoda Motohiro, Miyata Toshio, Ogawa Akiya, Tsujita Tadayuki
  • Journal Title: Molecules Volume: 23 Issue: 4 Pages: 885-885
  • DOI: 10.3390/molecules23040885
  • Peer Reviewed / Open Access
• [Journal Article] New direction of PAI-1 inhibitor development: Clinical application to cancer treatment (2018)
  • Author(s): DAN Takashi、UCHIDA Wataru、HIRATSUKA Hideaki、OSHIMA Yoshiteru、MIYATA Toshio
  • Journal Title: Japanese Journal of Thrombosis and Hemostasis Volume: 29 Issue: 5 Pages: 487-494
  • DOI: 10.2491/jjsth.29.487
  • ISSN: 0915-7441, 1880-8808