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Investigation on biological activity of cyclic dinucleotides and elucidation of mechanism how the activity is expressed, directing toward invention of new immunostimulants

Research Project

Project/Area Number 24350087
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Chemistry related to living body
Research InstitutionAichi Institute of Technology

Principal Investigator

Hayakawa Yoshihiro  愛知工業大学, 工学部, 教授 (50022702)

Co-Investigator(Kenkyū-buntansha) Nishimura Akiko  愛知工業大学, 工学部, 准教授 (90609322)
Ohta Michio  椙山女学園大学, 看護学部, 教授 (20111841)
Hyodo Mamoru  愛知工業大学, 工学部, 講師 (30548186)
Project Period (FY) 2012-04-01 – 2016-03-31
Project Status Completed (Fiscal Year 2015)
Budget Amount *help
¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000)
Fiscal Year 2015: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2014: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2013: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2012: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Keywords環状ジヌクレオチド / c-di-GMP / 2',3'-cGAMP / 免疫活性 / がん細胞増殖抑制 / STING / 免疫 / バイオフィルム / がん / ガン免疫療法 / がん免疫療法 / c[G(3'-5')pA(3'-5')p] / c[G(2'-5')pA(3'-5')p] / 核酸 / 癌 / Riboswitch / ワクチン / 生理活性
Outline of Final Research Achievements

We analyzed the physiological activity of bis (3'-5') cyclic diguanylic acid(c-di-GMP)and other cyclic dinucleotides having similar structure. Our results demonstrated the important bioactivity of c-di-GMP to inhibit the metastases of breast cancer and to attenuate experimental autoimmune encephalitis. During the immune response against cytosolic DNA, cyclic-GMP-AMP (cGAMP) was proposed to bind to an immunoreceptor called STING. Here we demonstrated that non-canonical cyclic dinucleotides 2',3'-cGAMP, which contains a single 2’-5’ phosphodiester bond, activated STING and induced the production of type I interferons.
These are valuable findings for the development of the research and our final goal ”invention of useful immunostimulator”.

Report

(5 results)
  • 2015 Annual Research Report   Final Research Report ( PDF )
  • 2014 Annual Research Report
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • Research Products

    (19 results)

All 2015 2014 2013 2012 Other

All Int'l Joint Research (1 results) Journal Article (16 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 16 results,  Open Access: 3 results,  Acknowledgement Compliant: 4 results) Presentation (2 results)

  • [Int'l Joint Research] Harvard Medical School/Georgia Cancer Center Augusta University/University of California, Berkley(米国)

    • Related Report
      2015 Annual Research Report
  • [Journal Article] Bacterial c-di-GMP affects hematopoietic stem/progenitors and their niches through STING.2015

    • Author(s)
      Kobayashi H, Kobayashi CI, Nakamura-Ishizu A, Karigane D, Haeno H, Yamamoto KN, Sato T, Ohteki T, Hayakawa Y, Barber GN, Kurokawa M, Suda T, and Takubo K.
    • Journal Title

      Cell Reports

      Volume: 111 Issue: 1 Pages: 71-84

    • DOI

      10.1016/j.celrep.2015.02.066

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Liposomes loaded with a STING pathway ligand, cyclic di-GMP, enhance cancer immunotherapy against metastatic melanoma.2015

    • Author(s)
      Nakamura T, Miyabe H, Hyodo M, Sato Y, Hayakawa Y, Harashima H.
    • Journal Title

      J Control Release

      Volume: 216 Pages: 149-157

    • DOI

      10.1016/j.jconrel.2015.08.026

    • NAID

      120005853062

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A new adjuvant delivery system ‘cyclic di-GMP/YSK05 liposome’ for cancer immunotherapy.2014

    • Author(s)
      Hiroko Miyabe, Mamoru Hyodo, Takashi Nakamura, Yusuke Sato, Yoshihiro Hayakawa, and Hideyoshi Harashima
    • Journal Title

      J. Controlled Release

      Volume: 184 Pages: 20-27

    • DOI

      10.1016/j.jconrel.2014.04.004

    • NAID

      120005512017

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Activation of the Stimulator of Interferon Genes (STING) adaptor attenuates experimental autoimmune encephalitis.2014

    • Author(s)
      Henrique Lemos, Lei Huang, Phillip R. Chandler, Eslam Mohamed, Guilherme R. Souza, Lingqian Li, Gabriela Pacholczyk, Glen N. Barber, Yoshihiro Hayakawa, David H. Munn, and Andrew L. Mellor
    • Journal Title

      J. Immunology

      Volume: 192 Issue: 12 Pages: 5571-5578

    • DOI

      10.4049/jimmunol.1303258

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] STING Ligand c-di-GMP Improves Cancer Vaccination against Metastatic Breast Cancer.2014

    • Author(s)
      Dinesh Chandra, Wilber Quispe-Tintaya, Arthee Jahangir, Denise Asafu-Adjei, Liyssa Ramos, Herman O. Sintim, Jie Zhou, Yoshihiro Hayakawa, David K. R. Karaolis, and Claudia Gravekamp
    • Journal Title

      Cancer Immunology Research

      Volume: 2 Issue: 9 Pages: 901-910

    • DOI

      10.1158/2326-6066.cir-13-0123

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] c-di-GMP Enhances Protective Innate Immunity in a Murine Model of Pertussis.2014

    • Author(s)
      S. Elahi, J. Van Kessel, T. G. Kiros, S. Strom, Y Hayakawa, M.Hyodo, L. A. Babiuk, and V. Gerdts
    • Journal Title

      PLOS ONE

      Volume: 9 Issue: 10 Pages: e109778-e109778

    • DOI

      10.1371/journal.pone.0109778

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] The innate DNA sensor cGAS produces a non-canonical cyclic-di-nucleotide that activates human STING.2013

    • Author(s)
      Elie J. Diner, Dara L. Burdette, Stephen C. Wilson, Kathryn M. Monroe, Colleen A. Kellenberger, Mamoru Hyodo, Yoshihiro Hayakawa, Ming C. Hammond, and Russell E. Vance
    • Journal Title

      Cell Reports

      Volume: 3 Issue: 5 Pages: 1355-1361

    • DOI

      10.1016/j.celrep.2013.05.009

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cutting Edge: DNA Sensing via the Stimulator of Interferon Genes (STING) Adaptor in Myeloid Dendritic Cells Induces Potent Tolerogenic Responses.2013

    • Author(s)
      abak Baban, Glen N. Barber, Yoshihiro Hayakawa, Tracy L. McGaha, David H. Munn, and Andrew L. Mellor
    • Journal Title

      J. Immunology

      Volume: 191 Pages: 3509-3513

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Development of an Efficient Short Interference RNA (siRNA) Delivery System with a New pH-Sensitive Cationic Lipid2012

    • Author(s)
      佐藤悠介
    • Journal Title

      YAKUGAKU ZASSHI

      Volume: 132 Issue: 12 Pages: 1355-1363

    • DOI

      10.1248/yakushi.12-00234-2

    • NAID

      130002489531

    • ISSN
      0031-6903, 1347-5231
    • Year and Date
      2012-12-01
    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] RIG-I detects infection with live Listeria by sensing secreted bacterial nucleic acids2012

    • Author(s)
      Zeinab Abdullah, et al.
    • Journal Title

      EMBO J.

      Volume: 31 Issue: 21 Pages: 4153-4164

    • DOI

      10.1038/emboj.2012.274

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Controlling glycosyl bond conformation of guanine nucleosides : stabilization of the anti conformer in 5'-O-ethylguanosine2012

    • Author(s)
      H.Asami, S.Urashima, M.Tsukamoto, A.Motoda, Y.Hayakawa, H.Saigusa
    • Journal Title

      Journal of Physical Chemistry Letters

      Volume: 3 Issue: 5 Pages: 571-575

    • DOI

      10.1021/jz300081e

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification of ligand Analogues that control c-di-GMP Riboswitches2012

    • Author(s)
      Kazuhiko Furukawa
    • Journal Title

      ACS Chem. Biol.

      Volume: 7 Issue: 8 Pages: 1436-1443

    • DOI

      10.1021/cb300138n

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A PixD-PapB Chimeric Protein Reveals the Function of the BLUF Domain C-Terminal a-Helices for Light Signal Transduction2012

    • Author(s)
      Shukun Ren, et al.
    • Journal Title

      Plant Cell Physiology

      Volume: 53 Issue: 9 Pages: 1638-1647

    • DOI

      10.1093/pcp/pcs108

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Vascular-targeted nanotherapy for obesity” Unexpected passive targeting mechanism to obese fat for the enhancement of active drug delivery.2012

    • Author(s)
      Hossen Md. Nazir
    • Journal Title

      Journal of Controlled Release

      Volume: 163 Issue: 2 Pages: 101-110

    • DOI

      10.1016/j.jconrel.2012.09.002

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A pH-sensitive cationic lipid facilitates the delivery of liposomal siRNA and gene silencing activity in vitro and in VIVO2012

    • Author(s)
      2. Sato Y, Hatakeyama H, Sakurai Y Hyodo M, Akita H, Harashima H
    • Journal Title

      Journal of Controlled Release

      Volume: 163 Issue: 3 Pages: 267-276

    • DOI

      10.1016/j.jconrel.2012.09.009

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Development of a novel DNA aptamer ligand against primary cultured tumor endothelial cell2012

    • Author(s)
      Naznin Ara.
    • Journal Title

      PLoS ONE

      Volume: 7(12) Issue: 12 Pages: e50174-e50174

    • DOI

      10.1371/journal.pone.0050174

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Presentation] Synthesis and biological activity of cG(2'–5')oA(3'–5')p2014

    • Author(s)
      Mamoru Hyodo, Masahito Inagaki, Hiroko Miyabe, Takashi Nakamura, Hideyoshi Harashima, and Yoshihiro Hayakawa
    • Organizer
      The 41st International Symposium on Nucleic Acids Chemistry 2014
    • Place of Presentation
      Kitakyushu, Japan
    • Year and Date
      2014-11-05 – 2014-11-07
    • Related Report
      2014 Annual Research Report
  • [Presentation] Synthesis and biological activity of cyclic dinucleotide diphosphorothioates2014

    • Author(s)
      Mamoru Hyodo, Shogo Ishiyama, Hiroaki Murai, Taichi Kamegaya, Michio Ohta, Stephen Lory, and Yoshihiro Hayakawa
    • Organizer
      The 41st International Symposium on Nucleic Acids Chemistry 2014
    • Place of Presentation
      Kitakyushu, Japan
    • Year and Date
      2014-11-05 – 2014-11-07
    • Related Report
      2014 Annual Research Report

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Published: 2012-04-24   Modified: 2022-01-27  

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