The development of a novel mechanism therapeutic drug for rare intractable inflammatory diseases

• Project/Area Number: 24249033
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Tohoku University
• Principal Investigator: MIYATA Toshio 東北大学, 医学(系)研究科(研究院), 教授 (10222332)
• Co-Investigator(Kenkyū-buntansha): DAN Takashi 東北大学, 医学系研究科, 准教授 (00512451)
• Co-Investigator(Renkei-kenkyūsha): ICHIMURA Atsuhiko 東北大学, 医学系研究科, 非常勤講師 (10609209)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥44,850,000 (Direct Cost: ¥34,500,000、Indirect Cost: ¥10,350,000); Fiscal Year 2014: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000); Fiscal Year 2013: ¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000); Fiscal Year 2012: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000)
• Keywords: 薬理学 / 生理活性 / 生体分子

Outline of Final Research Achievements

The study was performed to specify an adaptation of PAI-1 inhibitors which were effective and safe against rare intractable inflammatory diseases.
Finding bone marrow regeneration promoted by PAI-1 inhibitors in umbilical cord blood transplantation, led the doctor’s investigated phase 1 clinical trials. Non-clinical safety studies were carried out from the discovery of the efficacy in multiple sclerosis models.　Furthermore, as a result of PAI-1 inhibition in ovarian carcinoma cell lines, cell proliferation was suppressed by increasing the apoptosis and the G2/M phase cells. Moreover, the evaluation of the effects of PAI-1 inhibitors in bleomycin-induced lung fibrosis models, it was found that the lung hydroxyproline content was reduced significantly.

Research Products

• [Journal Article] Podocyte injury-driven intracapillary plasminogen activator inhibitor type 1 accelerates podocyte loss via uPAR-mediated β1-integrin endocytosis. (2015)
  • Author(s): Kobayashi N, Ueno T, Ohashi K, Yamashita H, Takahashi Y, Sakamoto K, Manabe S, Hara S, Takashima Y, Dan T, Pastan I, Miyata T, Kurihara H, Matsusaka T, Reiser J, Nagata M.
  • Journal Title: Am J Physiol Renal Physiol Volume: 308・6 Issue: 6 Pages: F614-F626
  • DOI: 10.1152/ajprenal.00616.2014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inhibition of plasminogen activator inhibitor-1 is a potential therapeutic strategy in ovarian cancer. (2015)
  • Author(s): Mashiko S, Kitatani K, Toyoshima M, Ichimura A, Dan T, Usui T, Ishibashi M, Shigeta S, Nagase S, Miyata T, Yaegashi N.
  • Journal Title: Cancer Biol Ther. Volume: 16 Pages: 253-260
  • Peer Reviewed
• [Journal Article] Small Molecule Inhibitors of PAI-1 TM5275 and TM5441 Elicit Anti-Angiogenic and Anti-tumorigenic. (2015)
  • Author(s): Placencio VR, Ichimura A, Miyata T, DeClerck YA.
  • Journal Title: Journal Molecular Cancer Therapeutics. Volume: 掲載確定
  • Peer Reviewed
• [Journal Article] Nitric oxide prevents alveolar senescence and emphysema in a mouse model (2015)
  • Author(s): Boe AE, Eren M, Morales-Nebreda L, Murphy SB, Budinger GR, Mutlu GM, Miyata T, Vaughan DE.
  • Journal Title: PLoS One. Volume: 10
  • Peer Reviewed
• [Journal Article] Plasminogen Activator Inhibitor-1 Antagonist TM5484 Attenuates Demyelination and Axonal Degeneration in a Mice Model of Multiple Sclerosis (2015)
  • Author(s): Pelisch N, Dan T, Ichimura A, Sekiguchi H, Vaughan DE, van Ypersele C, Miyata T.
  • Journal Title: PLoS One. Volume: 掲載確定
  • Peer Reviewed
• [Journal Article] Drug discovery in renal disease--towards a more efficient framework. (2014)
  • Author(s): Miyata T, Ando T, Hiragi H, Watanabe K, Yamamoto F, Vaughan DE, Kurokawa T, Oshima Y, van Ypersele de Strihou C, Takeuchi M.
  • Journal Title: Nat Rev Nephrol. Volume: 10 Issue: 5 Pages: 290-296
  • DOI: 10.1038/nrneph.2014.36
  • Peer Reviewed
• [Journal Article] PAI-1-regulated extracellular proteolysis governs senescence and survival in Klotho mice. (2014)
  • Author(s): Eren M, Boe AE, Murphy SB, Place AT, Nagpal V, Morales-Nebreda L, Urich D, Quaggin SE, Budinger GR, Mutlu GM, Miyata T, Vaughan DE.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 13 Issue: 19 Pages: 7090-7095
  • DOI: 10.1073/pnas.1321942111
  • Peer Reviewed
• [Journal Article] Inhibition of Plasminogen Activator Inhibitor Type-1 Activity Enhances Rapid and Sustainable Hematopoietic Regeneration. (2014)
  • Author(s): Ibrahim AA, Yahata T, Onizuka M, Dan T, van Ypersele de Strihou C, Miyata T, Ando K.
  • Journal Title: Stem Cells Volume: 32 Pages: 946-958
  • Peer Reviewed
• [Journal Article] A smoll molecule inhibitor to plasminogen activator inhibitor 1 inhibits macrophage migration. (2013)
  • Author(s): Ichimura A, Matsumoto S, Suzuki S, Dan T, Yamaki S, Sato Y, Kiyomoto H, Ishii N, Okada K, Matsuo O, Hou FF, Vaughan DE, van Ypersele de Strihou S, Miyata T.
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 33 Issue: 5 Pages: 935-942
  • DOI: 10.1161/atvbaha.113.301224
  • Peer Reviewed
• [Journal Article] TM5275prolongs secreted tissue plasminogen activator retention and enhancesfibrinolysis on vascular endothelial cells. (2013)
  • Author(s): Yasui H, Suzuki Y, Sano H, Suda T, Chida K, Dan T, Miyata T, Urano T
  • Journal Title: Thromb Res Volume: ## Issue: 1 Pages: 100-105
  • DOI: 10.1016/j.thromres.2013.04.003
  • Peer Reviewed
• [Journal Article] The PAI-1 antagonist TM5441 attenuates L-NAME-induced hypertension and vascular senescence (2013)
  • Author(s): Boe A, Eren M, Murphy S, Kamide1 C, Ichimura A, Terry D, McAnally D, Smith LH, Miyata T, Vaughan DE
  • Journal Title: Circulation Volume: 128 Issue: 21 Pages: 2318-2324
  • DOI: 10.1161/circulationaha.113.003192
  • Peer Reviewed
• [Journal Article] Kidney failure: aims for the next 10 years and barriers to success (2013)
  • Author(s): Remuzzi G, Benigni A, Finkelstein FO, Grunfeld JP, Joly D, Katz I, Liu ZH, Miyata T, Perico N, Rodriguez-Iturbe B, Antiga L, Schaefer F, Schieppati A, Schrier RW, Tonelli M
  • Journal Title: Lancet Volume: 382 Issue: 9889 Pages: 353-362
  • DOI: 10.1016/s0140-6736(13)60438-9
  • Peer Reviewed
• [Journal Article] Diabetic nephropathy: are there new and potentially promising therapies targeting oxygen biology? (2013)
  • Author(s): Miyata T, Suzuki N, van Ypersele de Strihou C
  • Journal Title: Kidney Int Volume: 84 Issue: 4 Pages: 693-702
  • DOI: 10.1038/ki.2013.74
  • Peer Reviewed
• [Journal Article] Renal failure worldwide: what we want to achieve in 10 year time and which barriers to overcome (2013)
  • Author(s): Giuseppe Remuzzi
  • Journal Title: Lancet Volume: 掲載確定
  • Peer Reviewed
• [Journal Article] A Small Molecule Inhibitor to Plasminogen Activator Inhibitor 1 Inhibits Macrophage Migration. (2013)
  • Author(s): Ichimura A
  • Journal Title: Arterioscler Thromb Vasc Biol. Volume: 掲載確定
  • Peer Reviewed
• [Journal Article] Therapeutic value of small molecule inhibitor to plasminogen activator inhibitor-1 for lung fibrosis. (2012)
  • Author(s): Huang WT
  • Journal Title: Am J Respir Cell Mol Biol Volume: 46 Issue: 1 Pages: 87-95
  • DOI: 10.1165/rcmb.2011-0139oc
  • Peer Reviewed
• [Journal Article] Inhibition of PAI-1 induces neutrophil-driven neoangiogenesis and promotes tissue regeneration via production of angiocrine factors in mice (2012)
  • Author(s): Yoshihiko Tashiro, Chiemi Nishida, Kaori Sato-Kusubata, Makiko Ohki-Koizumi, Makoto Ishihara, Aki Sato, Ismael Gritli, Hiromitsu Komiyama, Yayoi Sato, Takashi Dan, Toshio Miyata, Ko Okumura, Yuichi Tomiki, Kazuhiro Sakamoto, Hiromitsu Nakauchi, Beate Heissig, and Koichi Hattori.
  • Journal Title: Blood Volume: 119 Issue: 26 Pages: 6382-6393
  • DOI: 10.1182/blood-2011-12-399659
  • Peer Reviewed
• [Presentation] PAI-1分子: 新たな役割と臨床応用 (2013)
  • Author(s): 宮田敏男
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: さっぽろ芸文館（札幌市）
• [Presentation] 大学からの創薬：現状と課題 (2013)
  • Author(s): 宮田敏男
  • Organizer: 第52回日本薬学会東北支部大会
  • Place of Presentation: 東北大学川内北キャンパス（仙台市）
• [Presentation] アカデミア発創薬: 意義と課題 (2013)
  • Author(s): 宮田敏男、糸川昌成
  • Organizer: 第23回日本臨床精神神経薬理学会、第43回日本神経精神薬理学会
  • Place of Presentation: 沖縄コンベンションセンター（沖縄市）
• [Presentation] アカデミアからの新薬開発：意義と現状 (2013)
  • Author(s): 宮田敏男
  • Organizer: APSTJ2025WGシンポジウム（日本薬剤学会）
  • Place of Presentation: UDX Gallery NEXT（秋葉原、東京）
• [Presentation] Generation of Glyoxalase 1-deficient mouse (2012)
  • Author(s): Atsuhiko Ichimura
  • Organizer: 11th International Symposium on the Maillard Reaction
  • Place of Presentation: Nancy, France
• [Presentation] 大学からの創薬：現状と課題
  • Author(s): 宮田敏男
  • Organizer: 日本薬剤学会題27年会
  • Place of Presentation: 神戸
  • Invited
• [Presentation] 腎臓病学からの発信～先端創薬と早期探索臨床研究～
  • Author(s): 宮田敏男
  • Organizer: 旭川慢性
  • Place of Presentation: 旭川
  • Invited