The investigation of molecular mechanisms underlying refractory respiratory diseases and exploration of novel therapeutic targets

• Project/Area Number: 19209031
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: The University of Tokyo
• Principal Investigator: NAGASE Takahide The University of Tokyo, 医学部附属病院, 教授 (40208004)
• Co-Investigator(Kenkyū-buntansha): SHIMIZU Takao 東京大学, 大学院・医学系研究科, 教授 (80127092) ; KUHIHARA Hiroki 東京大学, 大学院・医学系研究科, 教授 (20221947) ; ISHI Satoshi 秋田大学, 大学院・医学系研究科, 教授 (10300815) ; TAKAI Daiya 東京大学, 医学部附属病院, 講師 (90361493)
• Project Period (FY): 2007 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥49,400,000 (Direct Cost: ¥38,000,000、Indirect Cost: ¥11,400,000); Fiscal Year 2010: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000); Fiscal Year 2009: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000); Fiscal Year 2008: ¥11,570,000 (Direct Cost: ¥8,900,000、Indirect Cost: ¥2,670,000); Fiscal Year 2007: ¥14,690,000 (Direct Cost: ¥11,300,000、Indirect Cost: ¥3,390,000)
• Keywords: 非閉塞性肺疾患癌 / 肺線維症 / 呼吸器感染症 / 肺炎症 / 脂質メディエーター / 転写因子 / 転写コアクチベーター / ノックアウトマウス / 脂質性メディエーター / 抗菌ペプチド / 生理活性ペプチド

Research Abstract

In respiratory diseases, there are several inflammatory disorders such as COPD, ARDS and pulmonary fibrosis, to which no pharmaceutical agents are currently effective. However, their mechanisms still remain to be elucidated. The purpose of this project is to investigate the roles of lipid mediators and TAZ in these disorders using genetically-engineered mice. We found that lipid mediators and TAZ were involved in the pathogenesis of inflammatory lung disorders. Our results suggest that these mediators might provide a novel therapeutic approach to these diseases.

Research Products

• [Journal Article] Amino acid residues critical for endoplasmic reticulum export and trafficking of platelet-activating factor receptor. (2010)
  • Author(s): Hirota N, Yasuda D, Hashidate T, Yamamoto T, Yamaguchi S, Nagamune T, Nagase T, Shimizu T, Nakamura M
  • Journal Title: J Biol Chem 19 : 285 Pages: 5931-5940
  • Peer Reviewed
• [Journal Article] Identification of GOS2 as a gene frequently methylated in squamous lung cancer by combination of in silico and experimental approaches. (2010)
  • Author(s): Kusakabe M, Kutomi T, Watanabe K, Emoto N, Aki N, Kage H, Hamano E, Kitagawa H, Nagase T, Sano A, Yoshida Y, Fukami T, Murakawa T, Nakajima J, Takamoto S, Ota S, Fukayama M, Yatomi Y, Ohishi N, Takai D
  • Journal Title: Int J Cancer 15 : 126 Pages: 1895-1902
  • Peer Reviewed
• [Journal Article] Tumor necrosis factor-alpha enhances both epithelial-mesenchymal transition and cell contraction induced in A549 human alveolar epithelial cells by transforming growth factor-beta1. (2010)
  • Author(s): Yamauchi Y, Kohyama T, Takizawa H, Kamitani S, Desaki M, Takami K, Kawasaki S, Kato J, Nagase T
  • Journal Title: Exp Lung Res 36 Pages: 12-24
  • Peer Reviewed
• [Journal Article] Histamine stimulates human lung fibroblast migration. (2010)
  • Author(s): Kohyama T, Yamauchi Y, Takizawa H, Kamitani S, Kawasaki S, Nagase T
  • Journal Title: Mol Cell Biochem 337 Pages: 77-81
  • Peer Reviewed
• [Journal Article] Histamine stimulates human lung fibroblast migration. (2010)
  • Author(s): Kohyama T, Yamauchi Y, Takizawa H, Kamitani S, Kawasaki S, Nagase T.
  • Journal Title: Mol Cell Biochem Volume: 337 Pages: 77-81
  • Peer Reviewed
• [Journal Article] Tumor necrosis factor-alpha enhances 'both epithelial-mesenchymal transition and cell contraction induced in A549 human alveolar epithelial cells by transforming growth factor-betal. (2010)
  • Author(s): Yamauchi Y, Kohyama T, Takizawa H, Kamitani S, Desaki M, Takami K, Kawasaki S, Kato J, Nagase T.
  • Journal Title: Exp Lung Res Volume: 36 Pages: 12-24
  • Peer Reviewed
• [Journal Article] Down-regulation of secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1(slurp-1), an endogenous allosteric alpha7 nicotinic acetylcholine receptor modulator, in murine ~and human asthmatic conditions. (2010)
  • Author(s): Narumoto O, Horiguchi K, Horiguchi S, Moriwaki Y, Takano-Ohmuro H, Shoji S, Misawa H, Yamashita N, Nagase T, Kawashima K, Yamashita N.
  • Journal Title: Biochem Biophys Res Commun Volume: 398 Pages: 713-718
  • Peer Reviewed
• [Journal Article] Transcriptional coactivator with PDZ-binding motif is essential for normal alveolarization in mice. (2009)
  • Author(s): Mitani A, Nagase T, Fukuchi K, Aburatani H, Makita R, Kurihara H
  • Journal Title: Am J Respir Crit Care Med 180 Pages: 326-338
  • Peer Reviewed
• [Journal Article] Thyroid transcription factor-1 inhibits transforming growth factor-beta-mediated epithelial-to-mesenchymal transition in lung adenocarcinoma cells. (2009)
  • Author(s): Saito RA, Watabe T, Horiguchi K, Kohyama T, Saitoh M, Nagase T, Miyazono K
  • Journal Title: Cancer Res 69 Pages: 2783-2791
  • Peer Reviewed
• [Journal Article] Impact of DNA demethylation of the G0S2 gene on the transcrip tion of G0S2 in squamous lung cancer cell lines with or without nuclear receptor agonists. (2009)
  • Author(s): Kusakabe M, Watanabe K, Emoto N, Aki N, Kage H, Nagase T, Nakajima J, Yatomi Y, Ohishi N, Takai D
  • Journal Title: Biochem Biophys Res Commun 390 Pages: 1283-1287
  • Peer Reviewed
• [Journal Article] Procaterol inhibits lung fibroblast migration. (2009)
  • Author(s): Kohyama T, Yamauchi Y, Takizawa H, Itakura S, Kamitani S, Desaki M, Kawasaki S, Nagase T
  • Journal Title: Inflammation 32 Pages: 387-392
  • Peer Reviewed
• [Journal Article] Transcriptional coactivator with PDZ-binding motif is essential for normal alveolarization in mice (2009)
  • Author(s): Mitani A, Nagase T, Fukuchi K, Aburatani H, Makita R, Kurihara H
  • Journal Title: Am J Respir Crit Care Med 180 Pages: 326-338
  • Peer Reviewed
• [Journal Article] Thyroid transcription factor-1 inhibits transforming growth factor-beta-mediated epithelial-to-mesenchymal transition in lung adenocarcinoma cells (2009)
  • Author(s): Saito RA, Watabe T, Horiguchi K, Kohyama T, Saitoh M, Nagase T, Miyazono K
  • Journal Title: Cancer Res 69 Pages: 2783-91
  • Peer Reviewed
• [Journal Article] Transcriptional coactivator with PDZ-binding motif is essential for normal alveolarization in mice. (2009)
  • Author(s): Mitani A, Nagase T, Fukuchi K, Aburatani H, Makita R, Kutihara H.
  • Journal Title: Am J Respir Crit Care Med 180 Pages: 326-338
  • Peer Reviewed
• [Journal Article] Thyroid transcription factor-1 inhibits transforming growth factor-beta-mediated epithelial-to-mesenchymal transition in lung adenocarcinoma cells. (2009)
  • Author(s): Saito RA, Watabe T, Horiguchi K, Kohyama T, Saitoh M, Nagase T, Miyazono K.
  • Journal Title: Cancer Res 69 Pages: 2783-91
  • Peer Reviewed
• [Journal Article] Renaltubular dysmorphogenesis leading to multicystic formation and lung emphysema in mice lacking TAZ. (2008)
  • Author(s): Makita R, Uchijima Y, Nishiyama K, Amano T, Chen Q, Takeuchi T, Mitani A, Nagase T, Yatomi Y, Aburatani H, Nakagawa O, Cobo-Stark P, Igarashi P, Murakami M, Tominaga J, Sato T, Asano T, Kurihara Y, Kurihara H
  • Journal Title: Am J Physiol 294
  • Peer Reviewed
• [Journal Article] Effect of dexamethasone on voltage-gated Na+ channel in cultured human bron chial smooth muscle cells. (2008)
  • Author(s): Nakajima T, Jo T, Meguro K, Ounuma H, Ma J, Kubota N, Imuta H, Takano H, Iida H, Nagase T , Nagata T.
  • Journal Title: Life Sci 825 Pages: 1210-1215
  • Peer Reviewed
• [Journal Article] Sequential and quantitative analysis of a murine model of elastase-induced emp hysema. (2008)
  • Author(s): Kawakami M, Matsuo Y, Yoshiura K, Nagase T, Yamashita N.
  • Journal Title: Biol Pharm Bull 31 Pages: 1434-1438
  • NAID: 110006792116
  • Peer Reviewed
• [Journal Article] Multiple renal cysts with concentration defects and pulmonary emphysema in mice lacking TAZ. (2008)
  • Author(s): Makita R, Uchijima Y, Nishiyama K, Amano T, Chen Q, Takeuchi T, Mitani A, Nagase T, Yatomi Y, Aburatani H, Nakagawa O, Cobo-Stark P, Igarashi P, Murakami M, Tominaga J, Sato T, Asano T, Kurihara Y, Kurihara H.
  • Journal Title: Am J Physiol 294
  • Peer Reviewed
• [Journal Article] Beta-defensin overexpression induces progressive muscle degeneration in mice. (2007)
  • Author(s): Yamaguchi Y, Nagase T, Tomita T, Nakamura K, Fukuhara S, Amano T, Yamamoto H, Ide Y, Suzuki M, Teramoto S, Asano T, Kangawa K, Nakagata N, Ouchi Y, Kurihara H
  • Journal Title: Am J Physiol Cell Physiol 292
  • Peer Reviewed
• [Journal Article] A second-generation profiling system for quantitative methylation analysis of multiple gene promoters : application to lung cancer. (2007)
  • Author(s): Sano A, Kage H, Sugimoto K, Kitagawa H, Aki N, Goto A, Fukuyama M, Nakajima J, Takamoto S, Nagase T, Yatomi Y, Ohishi N, Takai D
  • Journal Title: Oncogene 26 Pages: 6518-6525
  • Peer Reviewed
• [Journal Article] Impaired innate adrenomedullin function deteriorates airway hyperresponsiveness in mice: possible roles of allergen-induced airway wall remodeling. (2007)
  • Author(s): Yamamoto H, Nagase T, Shindo T, Teramoto S, Aoki-Nagase T, Yamaguchi Y, Yokomizo T, Nagai R, Kurihara H, Ouchi Y
  • Journal Title: J Appl Physiol 102 Pages: 2361-8
  • Peer Reviewed
• [Journal Article] Calcitonin gene-related peptide mediates acid-induced lung injury in mice. (2007)
  • Author(s): Aoki-Nagase T, Nagase T, Oh-hashi Y, Kurihara Y, Yamaguchi Y, Yamamoto H, Nagata T, Kurihara H, Ouchi Y
  • Journal Title: Respirology 12 Pages: 807-13
  • Peer Reviewed
• [Journal Article] The Induction of H3K9 Methylation by PIWIL4 at the p16Ink4a Locus. (2007)
  • Author(s): Sugimoto K, Kage H, Aki N, Sano A, Kitagawa H, Nagase T, Yatomi Y, Ohishi N, Takai D
  • Journal Title: Biochem Biophys Res Commun 359 Pages: 497-502
  • Peer Reviewed
• [Journal Article] 12-h pretreatment with methylprednisolone versus placebo for prevention of postextubation laryngeal oedema : a randomised double-blind trial (Correspondence letter) (2007)
  • Author(s): Goto Y, Nagase T
  • Journal Title: Lancet 370 Pages: 25-25
  • Peer Reviewed
• [Journal Article] Beta-defensin overexpression induces progressive muscle degeneration in mice (2007)
  • Author(s): Yamaguchi Y, Nagase T, Tomita T, Nakamura K, Fukuhara S, Amano T, Yamamoto H, Ide Y, Suzuki M, Teramoto S, Asano T, Kangawa K, Nakagata N, Ouchi Y, Kurihara H
  • Journal Title: Am J Physiol Cell Physiol 292
  • Peer Reviewed
• [Journal Article] Adrenomedullin insufficiency increases allergen induced airway hyperresponsiveness in mice (2007)
  • Author(s): Yamamoto H, Nagase T, Shindo T, Aoki-Nagase T, Nakamura K, Yamaguchi Y, Hanaoka Y, Kurihara H, Ouchi Y
  • Journal Title: J Appl Physiol 102 Pages: 2361-2368
  • Peer Reviewed
• [Journal Article] Calcitonin gene-related peptide mediates acid-induced lung injury in mice (2007)
  • Author(s): Aoki-Nagase T, Nagase T, Oh-hashi Y, Kurihara Y, Yamaguchi Y, Yamamoto H, Nagata T, Kurihara H, Ouchi Y
  • Journal Title: Respirology 12 Pages: 807-813
  • Peer Reviewed
• [Journal Article] Impaired innate adrenomedullin function deteriorates airway hyperresponsiveness in mice: possible roles of allergen-induced airway wall remodeling (2007)
  • Author(s): Yamamoto H, Naease T, Shindo T, Teramoto S, Aoki-Nagase T, Yamaguchi Y, Yokomizo T, Nagai R, Kurihara H, Ouchi Y
  • Journal Title: J Appl Physiol 102 Pages: 2361-2368
  • Peer Reviewed
• [Journal Article] Calcitonin gene-related peptide mediates acid-induced lung injury in mice (2007)
  • Author(s): Aoki-Nagase T, Naease T, Oh-hashi Y, Kurihara Y, Yamaguchi Y, Yamamoto H, Nagata T, Kurihara H, Ouchi Y
  • Journal Title: Respirology 12 Pages: 807-813
  • Peer Reviewed
• [Presentation] Respiratory research using genetically-engineered mice (2009)
  • Author(s): 長瀬隆英
  • Organizer: The14th APSR Meeting
  • Place of Presentation: Seoul
  • Year and Date: 2009-12-10
• [Presentation] Respiratory research using genetically-engineered mice (2009)
  • Author(s): 長瀬隆英
  • Organizer: The 14th APSR Meeting
  • Place of Presentation: Seoul,韓国
  • Year and Date: 2009-12-10
• [Presentation] Respiratory research using genetically-engineered mice. (2009)
  • Author(s): 長瀬隆英
  • Organizer: The 14th APSR Meeting Seoul.
  • Place of Presentation: ソウル、大韓民国(招待講演)
  • Year and Date: 2009-11-18
• [Presentation] 慢性閉塞性肺疾患 (2008)
  • Author(s): 長瀬隆英、教育企画
  • Organizer: 第50回日本老年医学会総会
  • Place of Presentation: 幕張
  • Year and Date: 2008-06-19
• [Presentation] 高齢者COPDの臨床 (2007)
  • Author(s): 長瀬隆英
  • Organizer: 第49回日本老年医学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2007-06-22
• [Presentation] 肺炎症における脂質性メディエーターに関して (2007)
  • Author(s): 長瀬隆英
  • Organizer: 第47回日本呼吸器学会総会
  • Place of Presentation: 東京(特別講演)
  • Year and Date: 2007-05-12
• [Presentation] 肺炎症における脂質性メディエーターに関して (2007)
  • Author(s): 長瀬隆英
  • Organizer: 第47回日本呼吸器学会総会 (特別講演)
  • Place of Presentation: 東京
  • Year and Date: 2007-05-12
• [Presentation] 肺炎症における脂質性メディエーターに関して (2007)
  • Author(s): 長瀬 隆英
  • Organizer: 第47回日本呼吸器学会総会(特別講演)
  • Place of Presentation: 東京
  • Year and Date: 2007-05-12
• [Patent(Industrial Property Rights)] 筋ジストロフィー症の病態モデル哺乳動物、及びその製造方法
  • Inventor(s): 栗原裕基, 大内尉義, 長瀬隆英, 山口泰弘