Development of new therapeutic strategies for chronic obstructive diseases using RNA interference

• Project/Area Number: 24591128
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Mie University
• Principal Investigator: GABAZZA Esteban 三重大学, 医学(系)研究科(研究院), 教授 (00293770)
• Co-Investigator(Kenkyū-buntansha): KOBAYASHI Tetsu 三重大学, 医学部附属病院, 講師 (20437114)
• Co-Investigator(Renkei-kenkyūsha): MORSER John 三重大学, 医学系研究科, 客員教授 (40571625)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 肺気腫 / 細胞内伝達機構 / NF-kappaB / RNA干渉 / プロテアーゼ / MMP-2 / 煙草 / 炎症性サイトカイン / COPD / 難病 / 気管支炎 / タバコ煙 / マウスモデル / ヒトマトリックスメタロプロテアーゼ / プロテアーゼ阻害剤 / 慢性炎症性疾患 / 転写因子 / 核酸医薬 / サイトカイン / ケモカイン

Outline of Final Research Achievements

In the present research project, we developed a novel metalloproteinase-(MMP-)2 transgenic mouse that showed characteristic findings of chronic obstructive pulmonary disease (COPD) after short-term exposure to inhaled cigarette smoke extracts. Wild type mice usually required exposure to cigarette smoke extracts of more than half-a-year to develop COPD typical findings in the lungs. In addition, this study evaluated the therapeutic usefulness of NF-kappaB siRNA in COPD using our present mouse model. Compared to control, intranasal administration of NF-kappaB siRNA significantly suppressed lung pathological changes, cell inflammation and inflammatory cytokines. The results of this study suggest the potential therapeutic usefulness of siRNA against NF-kappaB signal pathways in COPD.

Research Products

• [Journal Article] Protein S exacerbates alcoholic hepatitis by stimulating liver natural killer T cells. (2015)
  • Author(s): Chelakkot-Govindalayathil AL, Mifuji-Moroka R, D'Alessandro-Gabazza CN, Toda M, Matsuda Y, Gil-Bernabe P, Roeen Z, Yasuma T, Yano Y, Gabazza EC, Iwasa M, Takei Y.
  • Journal Title: J Thromb Haemost. Volume: １３（１） Issue: 1 Pages: 142-154
  • DOI: 10.1111/jth.12789
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Persistent release of IL-1s from skin is associated with systemic cardio-vascular disease, emaciation and systemic amyloidosis: the potential of anti-IL-1 therapy for systemic inflammatory diseases. (2014)
  • Author(s): Yamanaka K, Nakanishi T, Saito H, Maruyama J, Isoda K, Yokochi A, Imanaka-Yoshida K, Tsuda K, Kakeda M, Okamoto R, Fujita S, Iwakura Y, Suzuki N, Ito M, Maruyama K, Gabazza EC, Yoshida T, Shimaoka M, Mizutani H.
  • Journal Title: PLoS One. Volume: 9 Issue: 8 Pages: 104479-104479
  • DOI: 10.1371/journal.pone.0104479
  • Peer Reviewed / Open Access
• [Journal Article] Biologic therapy improves psoriasis by decreasing the activity of monocytes and neutrophils. (2014)
  • Author(s): Yamanaka K, Umezawa Y, Yamagiwa A, Saeki H, Kondo M, Gabazza EC, Nakagawa H, Mizutani H.
  • Journal Title: J Dermatol Volume: 41 Issue: 8 Pages: 679-85
  • DOI: 10.1111/1346-8138.12560
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Montelukast suppresses epithelial to mesenchymal transition of bronchial epithelial cells induced by eosinophils. (2014)
  • Author(s): Hosoki K, Kainuma K, Toda M, Harada E, Chelakkot-Govindalayathila AL, Roeen Z, Nagao M, D'Alessandro-Gabazza CN, Fujisawa T, Gabazza EC.
  • Journal Title: Biochem Biophys Res Commun Volume: 449 Issue: 3 Pages: 351-6
  • DOI: 10.1016/j.bbrc.2014.05.033
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Thrombomodulin modulates dendritic cells via both antagonism of high mobility group protein B1 and an independent mechanism. (2014)
  • Author(s): Toda M, D'Alessandro-Gabazza CN, Takagi T, Chelakkot-Govindalayathila AL, Taguchi O, Roeen Z, Munesue S, Yamamoto Y, Yamamoto H, Gabazza EC, Morser J.
  • Journal Title: Allergol Int Volume: 63 Pages: 57-66
  • NAID: 130004873109
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Differential gene expression in thrombomodulin (TM; CD141)(+) and TM(-) dendritic cell subsets. (2013)
  • Author(s): Toda M, Shao Z, Yamaguchi KD, Takagi T, D'Alessandro-Gabazza CN, Taguchi O, Salamon H, Leung LL, Gabazza EC, Morser J.
  • Journal Title: PLoS One. Volume: 8 Issue: 8 Pages: e72392-e72392
  • DOI: 10.1371/journal.pone.0072392
  • Peer Reviewed
• [Journal Article] Dose-dependent differential effects of thrombin in allergic bronchial asthma. (2013)
  • Author(s): Miyake Y, D'Alessandro-Gabazza CN, Takagi T, Naito M, Hataji O, Nakahara H, Yuda H, Fujimoto H, Kobayashi H, Yasuma T, Toda M, Kobayashi T, Yano Y, Morser J, Taguchi O, Gabazza EC.
  • Journal Title: J Thromb Haemost. Volume: 11 Issue: 10 Pages: 1903-1915
  • DOI: 10.1111/jth.12392
  • Peer Reviewed
• [Journal Article] Thrombin-activatable fibrinolysis inhibitor protects against acute lung injury by inhibiting the complement system. (2013)
  • Author(s): Naito M, Taguchi O, Kobayashi T, Takagi T, D'Alessandro-Gabazza CN, Matsushima Y, Boveda-Ruiz D, Gil-Bernabe P, Matsumoto T, Chelakkot-Govindalayathil AL, Toda M, Yasukawa A, Hataji O, Morser J, Takei Y, Gabazza EC.
  • Journal Title: Am J Respir Cell Mol Biol. Volume: 49 Issue: 4 Pages: 646-653
  • DOI: 10.1165/rcmb.2012-0454oc
  • Peer Reviewed
• [Journal Article] Eosinophils promote epithelial to mesenchymal transition of bronchial epithelial cells. (2013)
  • Author(s): Yasukawa A, Hosoki K, Toda M, Miyake Y, Matsushima Y, Matsumoto T, Boveda-Ruiz D, Gil-Bernabe P, Nagao M, Sugimoto M, Hiraguchi Y, Tokuda R, Naito M, Takagi T, D'Alessandro-Gabazza CN, Suga S, Kobayashi T, Fujisawa T, Taguchi O, Gabazza EC.
  • Journal Title: PLoS One Volume: 8 Issue: 5 Pages: 1-12
  • DOI: 10.1371/journal.pone.0064281
  • Peer Reviewed
• [Journal Article] Synthesis of18O-labeled RNA for application to kinetic studies and imaging. (2013)
  • Author(s): Hamasaki T, Matsumoto T, Sakamoto N, Shimahara A, Kato S, Yoshitake A, Utsunomiya A, Yurimoto H, Gabazza EC, Ohgi T.
  • Journal Title: Nucleic Acids Res. Volume: 41 Issue: 12 Pages: e126-e126
  • DOI: 10.1093/nar/gkt344
  • Peer Reviewed
• [Journal Article] Indacaterol improves daily physical activity in patients with chronic obstructive pulmonary disease. (2013)
  • Author(s): Hataji O, Naito M, Ito K, Watanabe F, Gabazza EC, Taguchi O.
  • Journal Title: Int J Chron Obstruct Pulmon Dis. Volume: 8 Pages: 1-5
  • DOI: 10.2147/copd.s38548
  • Peer Reviewed
• [Journal Article] Differential role of regulatory T cells in early and late stages of pulmonary fibrosis. (2013)
  • Author(s): Boveda-Ruiz D, D'Alessandro-Gabazza CN, Toda M, Takagi T, Naito M, Matsushima Y, Matsumoto T, Kobayashi T, Gil-Bernabe P, Chelakkot-Govindalayathil AL, Miyake Y, Yasukawa A, Morser J, Taguchi O, Gabazza EC.
  • Journal Title: Immunobiology. Volume: 218 Issue: 2 Pages: 245-254
  • DOI: 10.1016/j.imbio.2012.05.020
  • Peer Reviewed
• [Journal Article] Efficacy of a novel class of RNA interference therapeutic agents (2012)
  • Author(s): Hamasaki T, Suzuki H, Shirohzu H, Matsumoto T, D'Alessandro-Gabazza CN,Gil-Bernabe P, Boveda-Ruiz D, Naito M, Kobayashi T, Toda M, Mizutani T, TaguchiO, Morser J, Eguchi Y, Kuroda M, Ochiya T, Hayashi H, Gabazza EC, Ohgi T
  • Journal Title: PLoS One Volume: 7 Issue: 8 Pages: 1-15
  • DOI: 10.1371/journal.pone.0042655
  • Peer Reviewed
• [Presentation] The lung microbiome using mouse disease model (2014)
  • Author(s): Kobayashi Tetsu, Toda Masaaki, D’Alessandro- Gabazza Corina N., Takagi Takehiro, Chelakkot Govindalayathil Ayshwarya L., Roeen Ziaurahman, Urawa Masahito, Onishi Masahiro, Fujiwara Kentaro, Tomaru Atsushi, Taguchi Osamu, Gabazza Esteban
  • Organizer: 第43回日本免疫学会学術集会
  • Place of Presentation: 京都 国立京都国際会館
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] 薬剤中止にて迅速に改善したメサラジンによる薬剤性肺障害の1例 (2014)
  • Author(s): 藤原 研太郎、浦田 健太郎、都丸 敦史、高橋 佳紀、大西 真裕、高木 健裕、小林 哲、小林 裕康、田口 修、Esteban C. Gabazza
  • Organizer: 第124回日本結核病学会東海地方大会
  • Place of Presentation: 静岡 アクトシティ浜松コングレスセンター
  • Year and Date: 2014-11-29 – 2014-11-30
• [Presentation] A novel and short-term mouse model of chronic obstructive pulmonary disease (2014)
  • Author(s): O.Hataji,A.L.Chelakkot-Govindalayathil, C.N.D’Alessandro-Gabazza, M. Onishi, K. Fujiwara, M.Toda, T.Kobayashi, E.C.Gabazza, O. Taguchi.
  • Organizer: ERS Munich, Germany
  • Place of Presentation: ドイツ ミュンヘン
  • Year and Date: 2014-09-06 – 2014-09-10
• [Presentation] COPD治療における“可逆性”の可能性 (2014)
  • Author(s): 小林 哲、高橋 佳紀、都丸 敦史、藤原 研太郎、大西 真裕、高木 健裕、小林 裕康、Corina N. D’Alessandro-Gabazza、戸田 雅昭、Esteban C. Gabazza、田口 修
  • Organizer: 第88回閉塞性肺疾患研究会
  • Place of Presentation: 東京 大手町サンケイプラザ
  • Year and Date: 2014-07-19
• [Presentation] 気管支喘息における樹状細胞に対する活性化プロテインＣの役割 (2014)
  • Author(s): 高木健裕、高橋佳紀、都丸敦史、藤原研太郎、大西真裕、小林哲、小林裕康、ガバザ・エステバン、田口 修
  • Organizer: 第54回日本呼吸器学会
  • Place of Presentation: 大阪 国際会議場
  • Year and Date: 2014-04-26
• [Presentation] 呼吸器疾患におけるRNAiを用いた治療開発の可能性
  • Author(s): 小林哲、ガバザエステバン、その他
  • Organizer: 日本呼吸器学会
  • Place of Presentation: 東京国際フォーラム
• [Remarks] 基礎医学系講座 免疫学
  • URL: http://www.medic.mie-u.ac.jp/organization/course/immunology
• [Patent(Industrial Property Rights)] ヒトMMP2を発現するトランスジェニック非ヒト哺乳類動物 (2013)
  • Inventor(s): ガバザ エステバン, 田口 修, 小林 哲
  • Industrial Property Rights Holder: 三重大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2013-12-01