Challenge to novel antiviral strategy by suppressing signal transduction pathway

• Project/Area Number: 16K15258
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Experimental pathology
• Research Institution: Okayama University
• Principal Investigator: MATSUKAWA AKIHIRO 岡山大学, 医歯薬学総合研究科, 教授 (90264283)
• Research Collaborator: Yang Xu ; Sun Cuiming ; Gao Tong ; Miyatake Hideyuki ; Kondo Masayuki
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 感染症 / シグナル伝達抑制 / MAPKシグナル伝達 / ウイルス感染 / シグナル伝達

Outline of Final Research Achievements

In this study, we clarified the mechanism of viral infection from the viewpoint of Ras-Raf-ERK / MAPK and its endogenous suppressor Spred2, and we challenged the antiviral strategy via ERK suppression by supplementation of Spred2. Activation of ERK-MAPK and viral infection were suppressed by Spred2 gene transfer. There was no difference in virus infection in Spred2 overexpressing mice, suggesting that the endogenous Spred2 is sufficient to inhibit the infection. Cell-penetrating Spred2 created in this study failed to inhibit ERK activation, however, supplementation of functional Spred2 protein may become a new antiviral drug.

Academic Significance and Societal Importance of the Research Achievements

本研究課題により、Spred2導入によるウイルス感染制御を確認できた。Spred2過剰発現マウスの検討から、健常時は生来発現するSpred2により必要な抑制系は作動していると考えられた。本研究により、ヒトインフルエンザ感染血清や肺線維症肺での解析も実施できた。これらの疾患時に、膜透過性ペプチドを付加した機能性Spred2タンパクを補充できれば、汎用性の高い新しい抗ウイルス薬となる可能性が示唆された。これらの臨床データをもとに、新たな抗ウイルス戦略が期待できた意義は大きい。

Research Products

• [Journal Article] A Novel Combination Cancer Therapy with Iron Chelator Targeting Cancer Stem Cells via Suppressing Stemness. (2019)
  • Author(s): Yuki Katsura, Toshiaki Ohara, Kazuhiro Noma, Takayuki Ninomiya, Hajime Kashima, Takuya Kato, Hiroaki Sato, Satoshi Komoto, Toru Narusaka, Yasuko Tomono, Boyi Xing, Yuehua Chen, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Tomonari Kasai, Masaharu Seno, Akihiro Matsukawa and Toshiyoshi Fujiwara
  • Journal Title: Cancers Volume: 11 Issue: 67 Pages: 117-117
  • DOI: 10.18632/oncotarget.25973
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Spred2 Regulates High Fat Diet-Induced Adipose Tissue Inflammation, and Metabolic Abnormalities in Mice (2019)
  • Author(s): Ohkura T, Yoshimura T, Fujisawa M, Ohara T, Marutani R, Usami K, Matsukawa A
  • Journal Title: Front Immunol Volume: 10 Pages: 17-17
  • DOI: 10.3389/fimmu.2019.00017
  • NAID: 120006769768
  • Peer Reviewed / Open Access
• [Journal Article] Abrogated Caveolin-1 expression via histone modification enzyme Setdb2 regulates brain edema in a mouse model of influenza-associated encephalopathy. (2019)
  • Author(s): Imakita N, Kitabatake M, Ouji-Sageshima N, Hara A, Morita-Takemura S, Kasahara K, Matsukawa A, Wanaka A, Mikasa K, Ito T.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 284-284
  • DOI: 10.1038/s41598-018-36489-8
  • Peer Reviewed / Open Access
• [Journal Article] A Novel Combination Cancer Therapy with Iron Chelator Targeting Cancer Stem Cells via Suppressing Stemness (2019)
  • Author(s): Katsura Y, Ohara T, Noma K, Ninomiya T, Kashima H, Kato T, Sato H, Komoto S, Narusaka T, Tomono Y, Xing B, Chen Y, Tazawa H, Kagawa S, Shirakawa Y, Kasai T, Seno M, Matsukawa A, Fujiwara T
  • Journal Title: Cancers (Basel) Volume: 11(2) Issue: 2 Pages: 177-177
  • DOI: 10.3390/cancers11020177
  • NAID: 120006769762
  • Peer Reviewed / Open Access
• [Journal Article] Combined effect of anti-high-mobility group box-1 monoclonal antibody and peramivir against influenza A virus-induced pneumonia in mice (2019)
  • Author(s): Hatayama K, Nosaka N, Yamada M, Yashiro M, Fujii Y, Tsukahara H, Liu K, Nishibori M, Matsukawa A, Morishima T
  • Journal Title: J Med Virol Volume: 91 Issue: 3 Pages: 361-369
  • DOI: 10.1002/jmv.25330
  • Peer Reviewed
• [Journal Article] The relationship between the PD-L1 expression of surgically resected and fine-needle aspiration specimens for patients with pancreatic cancer. (2019)
  • Author(s): Matsumoto K, Ohara T, Fujisawa M, Takaki A, Takahara M, Tanaka N, Kato H, Horiguchi S, Yoshida R, Umeda Y, Fushimi S, Yagi T, Matsukawa A, Okada H
  • Journal Title: J Gastroenterol. Volume: Apr 29 Issue: 11 Pages: 1019-1028
  • DOI: 10.1007/s00535-019-01586-6
  • NAID: 120006839238
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SOCS3 overexpression in T cells ameliorates chronic airway obstruction in a murine heterotopic tracheal transplantation model. (2019)
  • Author(s): Mesaki K, Yamane M, Sugimoto S, Fujisawa M, Yoshimura T, Kurosaki T, Otani S, Oto S, Matsukawa A, Toyooka S
  • Journal Title: Surgery Today Volume: 49(5) Issue: 5 Pages: 443-450
  • DOI: 10.1007/s00595-018-1753-5
  • Peer Reviewed
• [Journal Article] Ovarian stromal cells as a source of cancer-associated fibroblasts in human epithelial ovarian cancer: A histopathological study (2018)
  • Author(s): Fujisawa M, Aye Moh-Moh-Aung, Zeng Z, Wani Y, Matsukawa A.
  • Journal Title: PLoS One Volume: 13(10) Issue: 10 Pages: e0205494-e0205494
  • DOI: 10.1371/journal.pone.0205494
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] SPRED2 deficiency may lead to lung ischemia-reperfusion injury via ERK1/2 signaling pathway activation (2018)
  • Author(s): Okada M, Yamane M, Yamamoto S, Otani S, Miyoshi K, Sugimoto S, Matsukawa A, Toyooka S, Oto T, Miyoshi S
  • Journal Title: Surg Today Volume: 48(12) Issue: 12 Pages: 1089-1095
  • DOI: 10.1007/s00595-018-1696-x
  • Peer Reviewed
• [Journal Article] Spred2 Deficiency Exacerbates D-Galactosamine/Lipopolysaccharide -induced Acute Liver Injury in Mice via Increased Production of TNFα (2018)
  • Author(s): Yang Xu、Fujisawa Masayoshi、Yoshimura Teizo、Ohara Toshiaki、Sato Miwa、Mino Megumi、San Thar Htet、Gao Tong、Kunkel Steven L.、Matsukawa Akihiro
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 917-917
  • DOI: 10.1038/s41598-017-18380-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Spred2-deficiecy Protects Mice from Polymicrobial Septic Peritonitis by Enhancing Inflammation and Bacterial Clearance (2017)
  • Author(s): Itakura Junya、Sato Miwa、Ito Toshihiro、Mino Megumi、Fushimi Soichiro、Takahashi Sakuma、Yoshimura Teizo、Matsukawa Akihiro
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 12833-12833
  • DOI: 10.1038/s41598-017-13204-7
  • Peer Reviewed / Open Access
• [Journal Article] Sprouty-Related Ena Vasodilator-Stimulated Phosphoprotein Homology 1-Domain Containing Protein-2 Critically Regulates Influenza A Virus Induced Pneumonia (2016)
  • Author(s): Toshihiro Ito, Junya Itakura, Sakuma Takahashi, Miwa Sato, Megumi Mino, Soichiro Fushimi, Masao Yamada, Tuneo Morishima, Steven L. Kunkel, Akihiro Matsukawa
  • Journal Title: Critical Care Medicine Volume: 44 Issue: 7 Pages: e530-e543
  • DOI: 10.1097/ccm.0000000000001562
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A Novel Role of Spred2 in the Colonic Epithelial Cell Homeostasis and Inflammation (2016)
  • Author(s): Takahashi S, Yoshimura T, Ohkura T, Fujisawa M, Fushimi S, Ito T, Itakura J, Hiraoka S, Okada H, Yamamoto K, Matsukawa A
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 37351-37351
  • DOI: 10.1038/srep37531
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Ras-Raf-ERK/MAPK経路とその制御因子Spred2による炎症・がんの制御 (2018)
  • Author(s): 松川昭博
  • Organizer: 第107回日本病理学会学術集会
  • Invited
• [Presentation] Spred-2 protects mice from ConA-induced liver injury. (2018)
  • Author(s): Sun C, Yshimura T, Fujisawa M, Ohara T, Yang Xu, Matsukawa A
  • Organizer: 第107回日本病理学会学術集会
• [Presentation] Spred2 deficiency exacerbates visceral adipose tissue inflammation and insulin resistance in mice. (2018)
  • Author(s): Ohkura T, Marutani R, Yoshimura T, Fujisawa M, Ohara T, Matsukawa A
  • Organizer: 第107回日本病理学会学術集会
• [Presentation] MiRNA-200b-3p may play a role in angiogenesis of hepatocellular carcinoma by targeting ERG (2018)
  • Author(s): Moh-Moh-Aung A. Fujisawa M, Yoshimura T, Matsukawa A
  • Organizer: 第107回日本病理学会学術集会
• [Presentation] The role of tumor cell-derived GM-CSF in the progression of 4T1 murine breast cancer. (2018)
  • Author(s): Yoshimura T, Nakamura K, Sato M, Li C, Fujisawa M, Mukaida N, Matsukawa A
  • Organizer: 第107回日本病理学会学術集会
• [Presentation] ヒト卵巣癌における線維芽細胞の由来 (2018)
  • Author(s): 藤澤真義、柳井広之、和仁洋治、伏見聡一朗、松川昭博
  • Organizer: 第107回日本病理学会学術集会
• [Presentation] ブレオマイシン肺線維症モデルにおけるSpred-2の役割 (2018)
  • Author(s): 河原明奈、水田亮、藤澤真義、吉村禎造、松川昭博
  • Organizer: 第107回日本病理学会学術集会
• [Presentation] 肺腺癌におけるSpred2の役割の解明 (2018)
  • Author(s): 太田陽子、藤澤真義、吉村禎造、Wayan SI, 阪口政清、豊岡伸一、松川昭博
  • Organizer: 第107回日本病理学会学術集会
• [Presentation] 胎児期に一過性骨髄異常増殖症を発症し胎盤にfetal thrombotic vasculopathyを伴ったダウン症候群の1例 (2018)
  • Author(s): 濱崎友洋、藤澤真義、伏見聡一郎、堀田真智子、苗村智、和仁洋治、宮原宏幸、吉村禎造、松川昭博
  • Organizer: 第107回日本病理学会学術集会
• [Presentation] Spred2 deficiency exacerbates adipose tissue inflammation and systemic insulin resistance in mice (2018)
  • Author(s): Ohkura T, Yoshimura T, Matsukawa A
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] Spred-2 protects mice from ConA-induced liver injury. (2017)
  • Author(s): Sun C, Yoshimura T, Fujisawa M, Ohara T, Xu Y, Matsukawa A.
  • Organizer: Cytokine 2017
  • Int'l Joint Research
• [Presentation] Spred-2 deficiency exacerbates lipopolysaccharide(LPS)/D-galctosamine (D-GalN) nduced liver injury. (2017)
  • Author(s): Xu Y, shimura T, Fujisawa M, Ohara T, Sun C, Matsukawa A
  • Organizer: Cytokine 2017
  • Int'l Joint Research
• [Presentation] 膀胱腫瘍におけるRas-ERK経路とその制御因子Spred-2の解析 (2017)
  • Author(s): 3.小田晋輔、藤澤真義、吉村禎造、大原利章、河原明奈、山口隆廣、太田陽子、松川昭博
  • Organizer: 第106回日本病理学会総会
• [Presentation] Spred-２欠損はGalN/LPS誘導性の急性肝障害を悪化させる (2017)
  • Author(s): 楊旭、吉村禎造、藤澤真義、大原利章、佐藤美和、美野愛、松川昭博
  • Organizer: 第106回日本病理学会総会
• [Presentation] 間質性肺炎モデルにおけるSpred-2の役割 (2017)
  • Author(s): 河原明奈、藤澤真義、吉村禎造、松川昭博
  • Organizer: 第106回日本病理学会総会
• [Presentation] Spred-2欠損はGalN/LPS誘導性の急性腎障害を悪化させる (2016)
  • Author(s): 楊旭、吉村禎造、藤澤真義、山口隆廣、小田晋輔、佐藤美和、美野愛、松川昭博
  • Organizer: 第37回日本炎症再生医学会
  • Place of Presentation: 京都
  • Year and Date: 2016-06-16
• [Presentation] Spred-2による炎症の制御 (2016)
  • Author(s): 松川昭博
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2016-05-12
  • Invited
• [Presentation] Spred-2欠損はGalN/LPS誘導性の急性腎障害を悪化させる (2016)
  • Author(s): 楊旭、吉村禎造、藤澤真義、大原利章、山口隆廣、タテサン、小田晋輔、佐藤美和、美野愛、松川昭博
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2016-05-12
• [Presentation] Spred-2欠損によるシスプラチン腎障害憎悪における好中球の関与 (2016)
  • Author(s): 藤井裕生、何佳利、吉村禎造、藤澤真義、佐藤美和、楊旭、松川昭博
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2016-05-12
• [Patent(Industrial Property Rights)] 徐放性デバイス (2018)
  • Inventor(s): 松川昭博、菅生健
  • Industrial Property Rights Holder: 松川昭博、菅生健
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018