RNA interference for the therapy of pulmonary hypertension

• Project/Area Number: 25461154
• 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: Taguchi Osamu 三重大学, 保健管理センター, 教授 (90197244)
• Co-Investigator(Kenkyū-buntansha): Gabazza Esteban 三重大学, 医学系研究科, 教授 (00293770)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肺高血圧症 / RNA干渉 / 転写因子 / ペリオスチン / 肺線維症 / 慢性閉塞性肺疾患 / 肺気腫 / 核酸 / ＮＦkappaB / ＥＴ-１ / 難病 / off-target / 内皮細胞障害 / エンドセリン受容体 / エンドセリン / 炎症 / 核酸siRNA干渉 / エントセリン / エントセリンレセプター / 動物モデル / モノクロタリン / サイトカイン

Outline of Final Research Achievements

Pulmonary hypertension may be of unknown etiology or caused by underlying disorders including emphysema, lung fibrosis or thromboembolism. This study evaluated the usefulness of RNA interference against NF-kappaB and periostin for pulmonary hypertension associated with lung fibrosis and emphysema. Cigarette smoke extract significantly increased the expression of endothelin and its receptors in pulmonary epithelial cells. Mice with emphysema was treated with siRNA against NF-kappaB. Alveolar wall destruction and lung inflammation were significantly suppressed by NF-kappaB siRNA compared to untreated mice. In addition, periostin siRNA significantly inhibited the development of fibrosis compared to control RNA. Overall, the results of this investigation clearly demonstrated the usefulness of siRNA therapy against transcription factor and matrix protein for the treatment of diseases that frequently lead to the development of pulmonary hypertension.

Research Products

• [Journal Article] Associations among circulating branched-chain amino acids and tyrosine with muscle volume and glucose metabolism in individuals without diabetes. (2016)
  • Author(s): Honda T, Kobayashi Y, Togashi K, Hasegawa H, Iwasa M, Taguchi O, Takei Y, Sumida Y.
  • Journal Title: Nutrition Volume: 32 Issue: 5 Pages: 531-538
  • DOI: 10.1016/j.nut.2015.11.003
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Thrombomodulin inhibits the activation of eosinophils and mast cells. (2015)
  • Author(s): Roeen Z, Toda M, D'Alessandro-Gabazza CN, Onishi M, Kobayashi T, Yasuma T, Urawa M, Taguchi O, Gabazza EC.
  • Journal Title: Cell Immunol. Volume: 293 Issue: 1 Pages: 34-40
  • DOI: 10.1016/j.cellimm.2014.11.005
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Activated protein C modulates the proinflammatory activity of dendritic cells. (2015)
  • Author(s): Matsumoto T, Matsushima Y, Toda M, Roeen Z, D'Alessandro-Gabazza CN, Hinneh JA, Harada E, Yasuma T, Yano Y, Urawa M, Kobayashi T, Taguchi O, Gabazza EC.
  • Journal Title: J Asthma Allergy Volume: 8 Pages: 29-37
  • DOI: 10.2147/jaa.s75261
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Influence of dietary intake of fish oil, magnesium, and zinc on metabolic parameters among individuals tested for diabetes. (2015)
  • Author(s): Takagi H, Kobayashi Y, Taguchi O, Takei Y, Sumida Y.
  • Journal Title: Nutrition Volume: 31 Issue: 7-8 Pages: 988-993
  • DOI: 10.1016/j.nut.2015.02.019
  • Peer Reviewed / Int'l Joint Research
• [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: Allergology International Volume: 63 Issue: 1 Pages: 57-66
  • DOI: 10.2332/allergolint.13-OA-0595
  • NAID: 130004873109
  • ISSN: 1323-8930, 1440-1592
  • Peer Reviewed / Open Access
• [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] A new strategy for healthcare-associated pneumonia: a 2-year prospective multicenter cohort study using risk factors for multidrug-resistant pathogens to select initial empiric therapy. (2013)
  • Author(s): Maruyama T, Fujisawa T, Okuno M, Toyoshima H, Tsutsui K, Maeda H, Yuda H, Yoshida M, Kobayashi H, Taguchi O, Gabazza EC, Takei Y, Miyashita N, Ihara T, Brito V, Niederman MS.
  • Journal Title: Clin Infect Dis. Volume: 57 Issue: 10 Pages: 1373-1383
  • DOI: 10.1093/cid/cit571
  • 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] 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
• [Presentation] Targeting Periostin for the Treatment of Pulmunary Fibrosis. (2015)
  • Author(s): 6.Gabazza EC, Kobayashi T, D’Alessandro-Gabazza CN, Toda M, Roeen Z, Takahashi Y, Fujiwara K, Hinneh JA, Yasuma T, Taguchi O.
  • Organizer: 9th International Symposium on Nanomedicine
  • Place of Presentation: 三重大学（三重県・津市）
  • Year and Date: 2015-12-10
  • Int'l Joint Research
• [Presentation] Matrix metalloproteinase-2 is protective in bleomycin-induced pulmonary fibrosis. (2015)
  • Author(s): 1.Tomaru A, Gabazza E, Kobayashi T, Kobayashi H, Taguchi O, Takagi T, Oonishi M, Fujiwara K, D'Alessandro Gabazza C, Takahashi Y, Urata K.
  • Organizer: International Conference of the European Respiratory Society
  • Place of Presentation: オランダ アムステルダム
  • Year and Date: 2015-09-26
  • Int'l Joint Research
• [Presentation] Lung overexpression of matrix metalloproteinase-2 protects against bronchial asthma. (2015)
  • Author(s): 2.Fujiwara K, Urata K, Tomaru A, Takahashi Y, Onishi M, Takehiro Takagi, Kobayashi H, D'Alessandro Gabazza CN, Gabazza EC, Taguchi O, Kobayashi T.
  • Organizer: International Conference of the European Respiratory Society
  • Place of Presentation: オランダ アムステルダム
  • Year and Date: 2015-09-26
  • Int'l Joint Research
• [Presentation] The immunomodulatory activity of protein S protects against allergic airway inflammation. (2015)
  • Author(s): 3.Takahashi Y, Urata K, Tomaru A, Fujiwara K, Onishi M, Takagi T, Kobayashi H, D'Alessandro-Gabazza C, Gabazza E, Taguchi O, Kobayashi T.
  • Organizer: International Conference of the European Respiratory Society
  • Place of Presentation: オランダ アムステルダム
  • Year and Date: 2015-09-26
  • Int'l Joint Research
• [Presentation] Clinical significance of transcutaneous PCO2 in patients with obstructive sleep apnea syndrome. (2015)
  • Author(s): 4.Sakaguchi T, Hataji O, Saiki H, Gabazza EC, D'Alessandro-Gabazza C, Nishii Y, Kobayashi T, Taguchi O.
  • Organizer: International Conference of the European Respiratory Society
  • Place of Presentation: オランダ アムステルダム
  • Year and Date: 2015-09-26
  • Int'l Joint Research
• [Presentation] Clinical severity of chronic obstructive pulmonary disease is associated with bone mineral density. (2015)
  • Author(s): 5.Saiki H, Hataji O, Sakaguchi T, Gabazza EC, Nishii Y, D'Alessandro-Gabazza C, Kobayashi T, Taguchi O.
  • Organizer: International Conference of the European Respiratory Society
  • Place of Presentation: オランダ アムステルダム
  • Year and Date: 2015-09-26
  • Int'l Joint Research
• [Presentation] 非結核性抗酸菌に対する自然免疫について (2015)
  • Author(s): 小林 裕康、北岡 一樹、浦田 健太郎、高橋 佳紀、都丸 敦史、藤原 研太郎、大西 真裕、高木 健裕、小林 哲、ガバザ エステバン、田口 修
  • Organizer: 第55回日本呼吸器学会学術講演会
  • Place of Presentation: 東京国際フォーラム（東京都・千代田区）
  • Year and Date: 2015-04-17
• [Presentation] 気管支喘息におけるマトリックスメタロプロテアーゼ2の役割 (2015)
  • Author(s): 藤原 研太郎、小林 哲、浦田 健太郎、都丸 敦史、高橋 佳紀、大西 真裕、高木 健裕、小林 裕康、Esteban C Gabazza、田口 修
  • Organizer: 第55回日本呼吸器学会学術講演会
  • Place of Presentation: 東京国際フォーラム（東京都・千代田区）
  • Year and Date: 2015-04-17
• [Presentation] 新規COPD誘発マウスモデルの検討 (2015)
  • Author(s): 大西 真裕、小林 哲、浦田 健太郎、高橋 佳紀、都丸 敦史、藤原 研太郎、高木 健裕、
  • Organizer: 第55回日本呼吸器学会学術講演会
  • Place of Presentation: 東京国際フォーラム（東京都・千代田区）
  • Year and Date: 2015-04-17
• [Presentation] マウスモデルにおけるマトリックスメタロプロテアーゼ2(MMP-2)の肺線維化抑制効果の検討 (2015)
  • Author(s): 都丸 敦史、浦田 健太郎、高橋 佳紀、藤原 研太郎、大西 真裕、高木 健裕、小林 哲、小林 裕康、ガバザ エステバン、田口 修
  • Organizer: 第55回日本呼吸器学会学術講演会
  • Place of Presentation: 東京国際フォーラム（東京都・千代田区）
  • Year and Date: 2015-04-17
• [Presentation] PSG施行時のtcPCO2の推移について (2015)
  • Author(s): 畑地 治、ガバザ エステバン、伊藤 健太郎、内藤 雅大、田口 修
  • Organizer: 第55回日本呼吸器学会学術講演会
  • Place of Presentation: 東京国際フォーラム（東京都・千代田区）
  • Year and Date: 2015-04-17
• [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
• [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