遺伝子改変マウスを用いた慢性閉塞性肺疾患発症機序の解明と新治療法の開発

• 研究課題/領域番号: 21590133
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 環境系薬学
• 研究機関: 三重大学
• 研究代表者: 田口 修 三重大学, 大学院・医学系研究科, 准教授 (90197244)
• 研究分担者: 小林 哲 三重大学, 医学部附属病院, 講師 (20437114)
• 連携研究者: GABAZZA Esteban 三重大学, 大学院・医学系研究科, 教授 (00293770)
• 研究期間 (年度): 2009 – 2011
• 研究課題ステータス: 完了 (2011年度)
• 配分額: 4,550千円 (直接経費: 3,500千円、間接経費: 1,050千円); 2011年度: 780千円 (直接経費: 600千円、間接経費: 180千円); 2010年度: 1,820千円 (直接経費: 1,400千円、間接経費: 420千円); 2009年度: 1,950千円 (直接経費: 1,500千円、間接経費: 450千円)
• キーワード: 閉塞性肺疾患 / 煙草 / 高齢者 / 炎症性サイトカイン / プロテアーゼ / 肺胞破壊 / 炎症性細胞 / 肺気腫 / 樹状細胞 / マトリックスメタロプロテーゼ / サイトカイン / 活性かプロテインC / 気管支炎 / 慢性閉塞性肺疾患 / タバコ / 血管内皮細胞傷害 / 凝固系因子 / 肺胞上皮細胞傷害 / 活性化プロテインC / 肺傷害 / 凝固系 / トロンビン受容体 / T細胞 / 慢性気管支炎 / トロンビン

研究概要

本研究では閉塞性肺疾患(COPD)の病態形成に関わる樹状細胞や上皮細胞や炎症性細胞由来のサイトカイン、プロテアーゼの産生に対する活性化プロテインC(APC)とトロンボモジュリン(TM)の抑制効果が認められた。また、マトリックスメタロプロテアーゼ(MMP)-2及びトランスフォーミング増殖因子(TGF)β1トランスジェニック(TG)マウスを作成し、COPDにTGFβ1とMMP-2の関与が認められた。In vivo実験ではTGFβ1とMMP-2による肺病変に対するAPCとTMの抑制効果の検討は現在進行中である。

研究成果

• [雑誌論文] Correlation between circulating fibrocytes and activity and progression of interstitial lung diseases (2012)
  • 著者名/発表者名: Fujiwara A, Kobayashi H, Masuya M, Maruyama M, Nakamura S, Ibata H, Fujimoto H, Ohnishi M, Urawa M, Naito M, Takagi T, Kobayashi T, Gabazza EC, Takei Y, Taguchi O
  • 雑誌名: Respirology 巻: (in press)(掲載決定)
  • 査読あり
• [雑誌論文] Role of thrombin-activatable fibrinolysis inhibitor in allergic bronchial asthma (2012)
  • 著者名/発表者名: Fujiwara A, Taguchi O, Takagi T, D' Alessandro-Gabazza CN, Boveda-Ruiz D, Toda M, Yasukawa A, Matsushima Y, Miyake Y, Kobayashi H, Kobayashi T, Gil-Bernabe P, Naito M, Yoshida M, Morser J, Takei Y, Gabazza EC
  • 雑誌名: Lung 巻: 190 ページ: 189-198
  • 査読あり
• [雑誌論文] Development and preclinical efficacy of novel transforming growth factor-β1 short interfering RNAs for pulmonary fibrosis (2012)
  • 著者名/発表者名: D' Alessandro-Gabazza CN, Kobayashi T, Boveda-Ruiz D, Takagi T, Toda M, Gil-Bernabe P, Miyake Y, Yasukawa A, Matsuda Y, Suzuki N, Saito H, Yano Y, Fukuda A, Hasegawa T, Toyobuku H, Rennard SI, Wagner PD, Morser J, Takei Y, Taguchi O, Gabazza EC
  • 雑誌名: Am J Respir Cell Mol Biol 巻: 46 ページ: 397-406
  • 査読あり
• [雑誌論文] Role of Thrombin-Activatable Fibrinolysis Inhibitor in Allergic Bronchial Asthma (2011)
  • 著者名/発表者名: Atsushi Fujiwara
  • 雑誌名: Lung 巻: (掲載確定) 号: 2 ページ: 189-198
  • DOI: 10.1007/s00408-011-9337-9
  • 年月日: 2011-10-25
  • 査読あり
• [雑誌論文] Lung Radiofrequency Ablation for the Treatment of Unresectable Recurrent Non-Small-Cell Lung Cancer After Surgical Intervention (2011)
  • 著者名/発表者名: Hiroshi Kodama
  • 雑誌名: CardioVascular and Interventional Radiology 巻: (掲載確定) 号: 3 ページ: 563-569
  • DOI: 10.1007/s00270-011-0220-0
  • 年月日: 2011-07-06
  • 査読あり
• [雑誌論文] Solitary pulmonary nodule of benign metastasizing leiomyoma associated with primary lung cancer : a case report (2011)
  • 著者名/発表者名: Naito M, Kobayashi T, Yoshida M, Fujiwara K, Onishi M, Fujiwara A, Takagi T, Kobayashi H, Gabazza EC, Takei Y, Taguchi O
  • 雑誌名: J Med Case Reports 巻: 5 ページ: 500-500
  • 査読あり
• [雑誌論文] Inhibition ofallergic bronchial asthma by thrombomodulin is mediated by dendritic cells (2011)
  • 著者名/発表者名: Takagi T, Taguchi O, Toda M, Ruiz DB, Bernabe PG, D' Alessandro-Gabazza CN, Miyake Y, Kobayashi T, Aoki S, Chiba F, Yano Y, Conway EM, Munesue S, Yamamoto Y, Yamamoto H, Suzuki K, Takei Y, Morser J, Gabazza EC
  • 雑誌名: Am J Respir Crit Care Med 巻: 183 ページ: 31-42
  • 査読あり
• [雑誌論文] Solitary pulmonary nodule of benign metastasizing leiomyoma associated with primary lung cancer : a case report (2011)
  • 著者名/発表者名: Masahiro Naito
  • 雑誌名: Journal of Medical Case Reports 巻: 5 号: 1
  • DOI: 10.1186/1752-1947-5-500
  • 査読あり
• [雑誌論文] Community-acquired macrolide-resistant Mycoplasma pneumoniae pneumonia in patients more than 18 years of age (2011)
  • 著者名/発表者名: Naoyuki Miyashita
  • 雑誌名: Journal of Infection and Chemotherapy 巻: 1 号: 1 ページ: 114-8
  • DOI: 10.1007/s10156-010-0093-1
  • 査読あり
• [雑誌論文] Inhibition of allergic bronchial asthma by thrombomodulin is mediated by dendritic cells. (2011)
  • 著者名/発表者名: Takagi T, Taguchi O, 他
  • 雑誌名: American Journal of Respiratory and Critical Care Medicine 巻: 183 ページ: 31-42
  • 査読あり
• [雑誌論文] Efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in nursing home residents : double blind, randomised and placebo controlled trial (2010)
  • 著者名/発表者名: Maruyama T, Taguchi O, Niederman MS, Morser J, Kobayashi H, Kobayashi T, D' Alessandro-Gabazza C, Nakayama S, Nishikubo K, Noguchi T, Takei Y, Gabazza EC
  • 雑誌名: BMJ 巻: 340 ページ: 1004-1004
  • 査読あり
• [雑誌論文] Pulmonary hypertension is ameliorated in mice deficient in thrombin-activatable fibrinolysis inhibitor (2010)
  • 著者名/発表者名: Qin L, D' Alessandro-Gabazza CN, Aoki S, Gil-Bernabe P, Yano Y, Takagi T, Boveda-Ruiz D, Ramirez Marmol AY, San Martin Montenegro VT, Toda M, Miyake Y, Taguchi O, Takei Y, Morser J, Gabazza EC
  • 雑誌名: J Thromb Haemost 巻: 8 ページ: 808-816
  • 査読あり
• [雑誌論文] Community-acquired pneumonia and nursing home-acquired pneumonia in the very elderly patients (2010)
  • 著者名/発表者名: Maruyama T, Gabazza EC, Morser J, Takagi T, D' Alessandro-Gabazza C, Hirohata S, Nakayama S, Ramirez AY, Fujiwara A, Naito M, Nishikubo K, Yuda H, Yoshida M, Takei Y, Taguchi O
  • 雑誌名: Respir Med. 巻: 104 ページ: 584-92
  • 査読あり
• [雑誌論文] Development and Preclinical Efficacy of Novel Transforming Growth Factor-β1 siRNAs for Pulmonary Fibrosis (2010)
  • 著者名/発表者名: Corina N D'Alessandro-Gabazza
  • 雑誌名: American Journal of Respiratory Cell and Molecular Biology 巻: (掲載確定) 号: 3 ページ: 397-406
  • DOI: 10.1165/rcmb.2011-0158oc
  • 査読あり
• [雑誌論文] Pulmonary hypertension is ameliorated in mice deficient in thrombin-activatable fibrinolysis inhibitor. (2010)
  • 著者名/発表者名: Qin L, Taguchi O, 他
  • 雑誌名: Journal of Thrombosis and Haemostasis 巻: 8 ページ: 808-816
  • 査読あり
• [雑誌論文] Efficacy of 23-valent pneumococcal vaccine in preventing pneumonia and improving survival in nursing home residents : double blind, randomised and placebo controlled trial. (2010)
  • 著者名/発表者名: Maruyama T, Taguchi O, 他
  • 雑誌名: British Medical Journal 巻: 340 ページ: 1004-1004
  • 査読あり
• [雑誌論文] Community-acquired pneumonia and nursing home-acquired pneumonia in the very elderly patients. (2010)
  • 著者名/発表者名: Maruyama T, Taguchi O, 他
  • 雑誌名: Respiratory Medicine 巻: 104 ページ: 584-592
  • 査読あり
• [雑誌論文] Resection of mucinous lung adenocarcinoma presenting with intractable bronchorrhea. (2010)
  • 著者名/発表者名: Takao M, Taguchi O, 他
  • 雑誌名: Journal of Thoracic Oncology 巻: 5 ページ: 576-578
  • 査読あり
• [雑誌論文] Pulmonary hypertension is ameliorated in mice deficient in thrombin-activatable fibrinolysis inhibitor (2010)
  • 著者名/発表者名: Qin Liqiang
  • 雑誌名: J.Thromb Haemost. (印刷中)
  • 査読あり
• [雑誌論文] Community-acquired pneumonia and nursing home-acquired pneumonia in the very elderly patients (2010)
  • 著者名/発表者名: Maruyama Takaya
  • 雑誌名: Respir Med (印刷中)
  • 査読あり
• [雑誌論文] Direct effects of protein S in ameliorating acute lung injury (2009)
  • 著者名/発表者名: Takagi T, Taguchi O, Aoki S, Toda M, Yamaguchi A, Fujimoto H, Boveda-Ruiz D, Gil-Bernabe P, Ramirez AY, Naito M, Yano Y, D' Alessandro-Gabazza CN, Fujiwara A, Takei Y, Morser J, Gabazza EC
  • 雑誌名: J Thromb Haemost 巻: 7 ページ: 2053-2063
  • 査読あり
• [雑誌論文] The coagulation and protein C pathways in patients with sleep apnea (2009)
  • 著者名/発表者名: Takagi T, Morser J, Gabazza EC, Qin L, Fujiwara A, Naito M, Yamaguchi A, Kobayashi T, D' Alessandro-Gabazza CN, Boveda Ruiz D, Gil Bernabe P, Iwasaki Y, Takei Y, Taguchi O
  • 雑誌名: Lung 巻: 187 ページ: 209-213
  • 査読あり
• [雑誌論文] Presence of thrombin-activatable fibrinolysis inhibitor in Helicobacter pylori-associated gastro-duodenal disease (2009)
  • 著者名/発表者名: Ikeda A, Gabazza EC, Morser J, Imoto I, Kuroda M, D' Alessandro-Gabazza CN, Hara K, Ruiz DB, Bernabe PG, Katsurahara M, Toda M, Kobayashi Y, Yano Y, Sumida Y, Suzuki K, Taguchi O, Takei Y
  • 雑誌名: Helicobacter 巻: 14 ページ: 147-155
  • 査読あり
• [雑誌論文] Direct effects of protein S in ameliorating acute lung injury (2009)
  • 著者名/発表者名: Takagi Takehiro
  • 雑誌名: J Thromb Haemost 7 ページ: 2053-2063
  • 査読あり
• [学会発表] Nasal obstruction and bronchial asthma (2011)
  • 著者名/発表者名: Hiroyasu Kobayashi
  • 学会等名: American Thoracic Society
  • 発表場所: Convention Center, Denver, Colorado
  • 年月日: 2011-05-15
• [学会発表] New therapeutic strategy based on severity and multidrug resistance risk factors in healthcare associated pneumonia (2011)
  • 著者名/発表者名: Takaya Maruyama
  • 学会等名: American Thoracic Society
  • 発表場所: Convention Center, Denver, Colorado
  • 年月日: 2011-05-04
• [学会発表] 気管支喘息患者におけるthrombomodulin陽性樹状細胞の役割について/Inverse correlation of thrombomodulin-positive dendritic cells with airflow limitation in patients with allergic bronchial asthma (2011)
  • 著者名/発表者名: 高木健裕,田口修,内藤雅大,戸田雅昭,小林哲,三宅泰士, Boveda-Ruiz D, D' Alessandro-Gabazza, Morser J, Gabazza EC
  • 学会等名: 第40回日本免疫学会学術集会
  • 発表場所: 千葉幕張メッセ
• [学会発表] Role of the complement system in exacerbation of acute lung injury in Thrombin-Activatable fibrinolysis inhibitor-deficient mice (2011)
  • 著者名/発表者名: 内藤雅大,田口修,高木健裕,戸田雅昭,小林哲,三宅泰士, Boveda-Ruiz D, D' Alessandro-Gabazza, C, Gabazza EC
  • 学会等名: 第40回日本免疫学会学術集会
  • 発表場所: 千葉幕張メッセ
• [学会発表] Role of thrombin-activatable fibrinolysis inhibitor in lipopolysaccharide-induced acute lung injury (2011)
  • 著者名/発表者名: Naito M, Taguchi O, Takagi T, Kobayashi T, D' Alessandro-Gabazza CN, Gabazza EC.
  • 学会等名: European Respiratory Society International Congress
  • 発表場所: Amsterdam, Netherlands
• [学会発表] Effect of thrombin inhalation in a murine model of bronchial asthma (2011)
  • 著者名/発表者名: Takagi T, Onishi M, Naito M, Fujiwara A, Kobayashi T, Kobayashi H, D' Alessandro-Gabazza CN, Gabazza EC, Taguchi O.
  • 学会等名: European Respiratory Society International Congress
  • 発表場所: Amsterdam, Netherlands
• [学会発表] Deficiency of thrombion-activatable fibrinolysis inhibitor worsens bronchial asthma (2010)
  • 著者名/発表者名: Takagi T, Taguchi O, 他
  • 学会等名: 2010 American Thoraci Society International Conference
  • 発表場所: New Orleans(米国)
  • 年月日: 2010-05-19
• [学会発表] Protective effect of thrombomodulin-positive dendritic cells against murine asthma (2010)
  • 著者名/発表者名: Fujiwara A, Urawa M, Naito M, Takagi T, Ebihara A, Kobayashi T, Kobayashi H, D' Alessandro-Gabazza CN, Takei Y, Gabazza EC, Taguchi O.
  • 学会等名: European Respiratory Society International Congress
  • 発表場所: Barcelona, Spain
• [学会発表] Protective effect of thrombomodulin-positive dendritic cells against murine asthma (2010)
  • 著者名/発表者名: Naito M, Takagi T, Taguchi O, Toda M, Kobayashi H, Kobayashi T, Fujiwara A, D' Alessandro-Gabazza CN, Boveda-Ruiz D, Morser J and Gabazza EC.
  • 学会等名: The 14^<th> International Congress of Immunology
  • 発表場所: Kobe, Japan
• [学会発表] Thrombin regulates the immune response (2010)
  • 著者名/発表者名: Miyake Y, Toda M, Yasukawa A, D' Alessandro-Gabazza CN, Takagi T, Naito M, Boveda-Ruiz D, Morser J, Taguchi O, Gabazza EC.
  • 学会等名: The 14^<th> International Congress of Immunology
  • 発表場所: Kobe, Japan
• [学会発表] The role of regulatory T cells in lung fibrosis (2010)
  • 著者名/発表者名: Boveda-Ruiz D, Toda M, D' Alessandro-Gabazza CN, Gil-Bernabe P, Miyake Y, Yasukawa A, Naito M, Takagi T, Morser J, Taguchi O, Gabazza EC.
  • 学会等名: The 14^<th> International Congress of Immunology
  • 発表場所: Kobe, Japan
• [学会発表] Exogenous activated protein C ameliorates diabetic nephropathy (2010)
  • 著者名/発表者名: Gil-Bernabe P, Yano Y, D' Alessandro-Gabazza CN, Boveda-Ruiz D, Toda M, Miyake Y, Yasukawa A, Takagi T, Morser J, Taguchi O, Gabazza EC.
  • 学会等名: The 14^<th> International Congress of Immunology
  • 発表場所: Kobe, Japan
• [学会発表] Protective effect of thrombomodulin in a murine model of allergen-induced asthma (2010)
  • 著者名/発表者名: Takagi T, Taguchi O, Toda M, Kobayashi H, Kobayashi T, Fujiwara A, Naito M, D' Alessandro-Gabazza CN, Boveda-Ruiz D, Gil-Bernabe P, Morser J, Gabazza EC.
  • 学会等名: The 14^<th> International Congress of Immunology
  • 発表場所: Kobe, Japan
• [学会発表] Allergen-induced bronchial asthma in the factor V Leiden mouse (2010)
  • 著者名/発表者名: Yasukawa A, Toda M, Miyake Y, D' Alessandro-Gabazza CN, Boveda-Ruiz D, Takagi T, Naito M, Taguchi O, Morser J, Gabazza EC.
  • 学会等名: The 14^<th> International Congress of Immunology
  • 発表場所: Kobe, Japan
• [学会発表] Role of thrombin-activatable fibrinolysis inhibitor in lipopolysaccharide-induced acute lung injury (2010)
  • 著者名/発表者名: Naito M, Taguchi O, Takagi T, Toda M, Kobayashi T, Miyake Y, Boveda-Ruiz D, D' Alessandro-Gabazza CN, Morser J, Takei Y, Gabazza EC.
  • 学会等名: Congress of the International Society on Thrombosis and Haemostasis
  • 発表場所: Kyoto, Japan
• [学会発表] Protective role of protein S in liver fibrosis (2010)
  • 著者名/発表者名: Moroka R, Gil-Bernabe P, D' Alessandro-Gabazza CN, Boveda-Ruiz D, Toda M, Miyake Y, Yasukawa A, Naito M, Takagi T, Iwasa M, Taguchi O, Morser J, Takei Y, Gabazza EC.
  • 学会等名: Congress of the International Society on Thrombosis and Haemostasis
  • 発表場所: Kyoto, Japan
• [学会発表] Protective effect of thrombomodulin in a murine model of allergen-induced asthma (2010)
  • 著者名/発表者名: Takagi T, Taguchi O, Naito M, Toda M, Kobayashi T, Miyake Y, Boveda-Ruiz D, D' Alessandro-Gabazza CN, Morser J, Gabazza EC.
  • 学会等名: Congress of the International Society on Thrombosis and Haemostasis
  • 発表場所: Kyoto, Japan
• [学会発表] Thrombomodulin modulates maturation and antigen presentation of murine dendritic cells in vitro (2010)
  • 著者名/発表者名: Toda M, Takagi T, Taguchi O, Boveda-Ruiz D, Gil-Bernabe P, D' Alessandro-Gabazza CN, Miyake Y, Yasukawa A, Morser J, Gabazza EC.
  • 学会等名: Congress of the International Society on Thrombosis and Haemostasis
  • 発表場所: Kyoto, Japan
• [学会発表] Allergen-induced bronchial asthma in the factor V Leiden mouse (2010)
  • 著者名/発表者名: Miyake Y, Matsushima Y, D' Alessandro-Gabazza CN, Takagi T, Naito M, Boveda-Ruiz D, Gil-Bernabe P, Morser J, Taguchi O, Gabazza EC.
  • 学会等名: Congress of the International Society on Thrombosis and Haemostasis
  • 発表場所: Kyoto, Japan
• [学会発表] The role of thrombin in allergic bronchial bronchial asthma is mediated by dendritic cells (2010)
  • 著者名/発表者名: Miyake Y, Matsushima Y, D' Alessandro-Gabazza CN, Takagi T, Naito M, Boveda-Ruiz D, Gil-Bernabe P, Morser J, Taguchi O, Gabazza EC.
  • 学会等名: Congress of the International Society on Thrombosis and Haemostasis
  • 発表場所: Kyoto, Japan
• [学会発表] Protective role of thrombin-activatable fibrinolysis inhibitor in allergic bronchial asthma (2010)
  • 著者名/発表者名: Boveda-Ruiz D, D' Alessandro-Gabazza CN, Toda M, Gil-Bernabe P, Miyake Y, Yasukawa A, Matsushima Y, Naito M, Takagi T, Morser J, Taguchi O, Gabazza EC.
  • 学会等名: Congress of the International Society on Thrombosis and Haemostasis
  • 発表場所: Kyoto, Japan
• [学会発表] Protein Salters differentiation, maturation and antigen presentation of murine dendritic cells in vitro (2010)
  • 著者名/発表者名: Matsushima Y, Corina N. D' Alessandro-Gabazza, Takagi T, Naito M, Boveda-Ruiz D, Gil-Bernabe P, Taguchi O, Morser J, Gabazza EC.
  • 学会等名: Congress of the International Society on Thrombosis and Haemostasis
  • 発表場所: Kyoto, Japan
• [学会発表] Role of thrombin-activatable fibrinolysis inhibitor in bronchial asthma (2009)
  • 著者名/発表者名: Takagi Takehiro
  • 学会等名: European Respiratory Society
  • 発表場所: Vienna
  • 年月日: 2009-09-14
• [学会発表] Role of thrombin-activatable fibrinolysis inhibitor in bronchial asthma (2009)
  • 著者名/発表者名: Takagi T, Naito M, Fujiwara A, Fujimoto H, Ebihara A, Yasui H, Kobayashi T, Kobayashi H, D' Alessandro-Gabazza CN, Gabazza EC, Takei Y, Taguchi O.
  • 学会等名: European Respiratory Society International Congress
  • 発表場所: Vienna, Austria
• [学会発表] Effect of a thrombin inhibitor on murine bronchial asthma (2009)
  • 著者名/発表者名: Fujiwara A, Naito M, Takagi T, Ebihara A, Kobayashi T, Kobayashi H, D' Alessandro-Gabazza CN, Gabazza EC, Takei Y, Taguchi O.
  • 学会等名: European Respiratory Society International Congress
  • 発表場所: Vienna, Austria
• [備考]
  • URL: http://www.mie-u.ac.jp/
• [産業財産権] ヒトTGFβ1を発現するトランスジェニックマウス (2011)
  • 発明者名: 小林哲、Gabazza Esteban
  • 権利者名: 小林哲、Gabazza Esteban
  • 産業財産権番号: 2011-237166
  • 出願年月日: 2011-10-28