The investigation of genes related to refractory respiratory diseases and development of novel therapeutics

• Project/Area Number: 23249045
• 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 東京大学, 医学部附属病院, 教授 (40208004)
• Co-Investigator(Renkei-kenkyūsha): SHIMIZU TAKAO 東京大学, 大学院医学系研究科, 特任教授 (80127092)
• Project Period (FY): 2011-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥46,800,000 (Direct Cost: ¥36,000,000、Indirect Cost: ¥10,800,000); Fiscal Year 2015: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000); Fiscal Year 2014: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000); Fiscal Year 2013: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000); Fiscal Year 2012: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000); Fiscal Year 2011: ¥12,220,000 (Direct Cost: ¥9,400,000、Indirect Cost: ¥2,820,000)
• Keywords: ＣＯＰＤ / 肺線維症 / ARDS / 呼吸器内科学 / 呼吸器内科 / 肺炎症 / 転写コアクチベーター / siRNA / エイコサノイド

Outline of Final Research Achievements

In respiratory diseases, there are several refractory disorders such as COPD, ARDS and pulmonary fibrosis, to which no pharmaceutical agents are currently available or 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 these lung disorders. Our results suggest that these mediators might provide a novel therapeutic approach to these diseases.

Research Products

• [Journal Article] Interleukin-17A and Toll-Like Receptor 3 Ligand Poly(I:C) Synergistically Induced Neutrophil Chemoattractant Production by Bronchial Epithelial Cells. (2015)
  • Author(s): MatsuzakiH, Mikami Y, Yamauchi Y ,et al.
  • Journal Title: PLoS One Volume: 10 Issue: 10 Pages: 10-10
  • DOI: 10.1371/journal.pone.0141746
  • Peer Reviewed / Open Access
• [Journal Article] Hippo and TGF-β interplay in the lung field (2015)
  • Author(s): Saito A, Nagase T
  • Journal Title: Am J Physiol Lung Cell Mol Physiol Volume: 309(8) Issue: 8 Pages: L756-L767
  • DOI: 10.1152/ajplung.00238.2015
  • Peer Reviewed
• [Journal Article] Histone methylation-mediated silencing of miR-139 enhances invasion of non-small-cell lung cancer (2015)
  • Author(s): Kousuke Watanabe, Yosuke Amano, Rie Ishikawa, Mitsuhiro Sunohara, Hidenori Kage, Junji Ichinose, Atsushi Sano, Jun Nakajima, Masashi Fukayama, Yutaka Yatomi, Takahide Nagase, Nobuya Ohishi and Daiya Takai
  • Journal Title: Cancer Medicine Volume: 4 Issue: 10 Pages: 1573-82
  • DOI: 10.1002/cam4.505
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of clinical characteristics and outcomes between aspiration pneumonia and community-acquired pneumonia in patients with chronic obstructive pulmonary disease. (2015)
  • Author(s): Yamauchi Y, Yasunaga H, Matsui H, et al.
  • Journal Title: BMC Pulm Med Volume: 15 Issue: 1 Pages: 69-69
  • DOI: 10.1186/s12890-015-0064-5
  • Peer Reviewed / Open Access
• [Journal Article] Oncogenic activity of BIRC2 and BIRC3 mutants independent of nuclear factor-κB-activating potential. (2015)
  • Author(s): Yamato A, Soda M, Ueno T, Kojima S, Sonehara K, Kawazu M, Sai E, Yamashita Y, Nagase T, Mano H.
  • Journal Title: Cancer Sci. Volume: 106 Issue: 9 Pages: 1137-42
  • DOI: 10.1111/cas.12726
  • Peer Reviewed / Open Access
• [Journal Article] Role of α1 and α2 chains of type IV collagen in early fibrotic lesions of idiopathic interstitial pneumonias and migration of lung fibroblasts. (2015)
  • Author(s): Urushiyama H, Terasaki Y, Nagasaka S, Terasaki M, Kunugi S, Nagase T, Fukuda Y, Shimizu A.
  • Journal Title: Lab Invest Volume: 95 Issue: 8 Pages: 872-885
  • DOI: 10.1038/labinvest.2015.66
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of in-hospital mortality in patients with COPD, asthma and asthma-COPD overlap exacerbations. (2015)
  • Author(s): Yamauchi Y, Yasunaga H, Matsui H, et al.
  • Journal Title: Respirology Volume: 20 Issue: 6 Pages: 940-946
  • DOI: 10.1111/resp.12556
  • Peer Reviewed
• [Journal Article] Ovary-dependent emphysema augmentation and osteopontin induction in adult female mice. (2015)
  • Author(s): Niikura Y, Ishii T, Hosoki K, Nagase T, Yamashita N.
  • Journal Title: Biochem Biophys Res Commun. Volume: 461 Issue: 4 Pages: 642-7
  • DOI: 10.1016/j.bbrc.2015.04.081
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Factors that predict in-hospital mortality in eosinophilic granulomatosis with polyangiitis. (2015)
  • Author(s): Hasegawa W, Yamauchi Y, Yasunaga H, Sunohara M, Jo T, Matsui H, Fushimi K, Takami K, Nagase T
  • Journal Title: Allergy. Volume: 70 Issue: 5 Pages: 585-90
  • DOI: 10.1111/all.12597
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Oncogenic TPM3-ALK activation requires dimerization through the coiled-coil structure of TPM3 (2015)
  • Author(s): Amano Y, Ishikawa R, Sakatani T, Ichinose J, Sunohara M, Watanabe K, Kage H, Nakajima J, Nagase T, Ohishi N, Takai D
  • Journal Title: Biochem Biophys Res Commun Volume: 13 Issue: 3 Pages: 457-60
  • DOI: 10.1016/j.bbrc.2015.01.014
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Lymphotoxin β receptor signaling induces IL-8 production in human bronchial epithelial cells. (2014)
  • Author(s): Mikami Y, Matsuzaki H, Horie M, Noguchi S, Jo T, Narumoto O, Kohyama T, Takizawa H, Nagase T, Yamauchi Y.
  • Journal Title: PLoS One Volume: 9 Issue: 12 Pages: 1-21
  • DOI: 10.1371/journal.pone.0114791
  • Peer Reviewed / Open Access
• [Journal Article] Alternative polyadenylation is associated with lower expression of PABPN1 and poor prognosis in non-small cell lung cancer. (2014)
  • Author(s): Ichinose J, Watanabe K, Sano A, Nagase T, Nakajima J, Fukayama M, Yatomi Y, Ohishi N, Takai D.
  • Journal Title: Cancer Sci Volume: 105 Issue: 9 Pages: 1135-1141
  • DOI: 10.1111/cas.12472
  • Peer Reviewed / Open Access
• [Journal Article] Novel swine model of transfusion-related acute lung injury. (2014)
  • Author(s): Okazaki H, Ishikawa O, Iijima T, Kohira T, Teranishi M, Kawasaki S, Saito A, Mikami Y, Sugiura A, Hashimoto S, Shimada E, Uchikawa M, Matsuhashi M, Tsuno NH, Tanaka M, Kiyokawa N, Fujimoto J, Nagase T, Tadokoro K, Takahashi K.
  • Journal Title: Transfusion. Volume: 54 Issue: 12 Pages: 3097-3107
  • DOI: 10.1111/trf.12766
  • Peer Reviewed
• [Journal Article] An integrative analysis of the tumorigenic role of TAZ in human non-small cell lung cancer. (2014)
  • Author(s): 3.Noguchi S, Saito A, Horie M, Mikami Y, Suzuki HI, Morishita Y, Ohshima M, Abiko Y, Mattsson JS, König H, Lohr M, Edlund K, Botling J, Micke P, Nagase T
  • Journal Title: Clin Cancer Res. Volume: 20 Issue: 17 Pages: 4660-72
  • DOI: 10.1158/1078-0432.ccr-13-3328
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Selective inhibitors of a PAF biosynthetic enzyme lysophosphatidylcholine acyltransferase 2. (2014)
  • Author(s): 4.Tarui M, Shindou H, Kumagai K, Morimoto R, Harayama T, Hashidate T, Kojima H, Okabe T, Nagano T, Nagase T, Shimizu T.
  • Journal Title: J Lipid Res. Volume: 55 Pages: 1386-96
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Histamine induces human lung fibroblast-mediated collagen gel contraction via histamine H1 receptor. (2014)
  • Author(s): 5.Horie M, Saito A, Yamauchi Y, Mikami Y, Sakamoto M, Jo T, Nakajima J, Takizawa H, Nagase T, Kohyama T.
  • Journal Title: Exp Lung Res. Volume: 40 Issue: 5 Pages: 222-36
  • DOI: 10.3109/01902148.2014.900155
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Differential knockdown of TGF-β ligands in a three-dimensional co-culture tumor- stromal interaction model of lung cancer. (2014)
  • Author(s): 6.Horie M, Saito A, Noguchi S, Yamaguchi Y, Ohshima M, Morishita Y, Suzuki HI, Kohyama T, Nagase T.
  • Journal Title: BMC Cancer. Volume: 14 Issue: 1 Pages: 580-580
  • DOI: 10.1186/1471-2407-14-580
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MxA transcripts with distinct first exons and modulation of gene expression levels by single-nucleotide polymorphisms in human bronchial epithelial cells. (2013)
  • Author(s): Noguchi S, Hijikata M, Hamano E, Matsushita I, Ito H, Ohashi J, Nagase T, Keicho N.
  • Journal Title: Immunogenetics Volume: 65 Issue: 2 Pages: 107-114
  • DOI: 10.1007/s00251-012-0663-8
  • Peer Reviewed
• [Journal Article] Differential effects of a common splice site polymorphism on the generation of OAS1 variants in human bronchial epithelial cells. (2013)
  • Author(s): Noguchi S, Hamano E, Matsushita I, Hijikata M, Ito H, Nagase T, Keicho N.
  • Journal Title: Hum Immunol Volume: 74 Issue: 3 Pages: 395-401
  • DOI: 10.1016/j.humimm.2012.11.011
  • Peer Reviewed
• [Journal Article] Effect of secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related peptide-1 (SLURP-1) on airway epithelial cells. (2013)
  • Author(s): Narumoto O, Niikura Y, Ishii S, Morihara H, Okashiro S, Nakahari T, Nakano T, Matsumura H, Shimamoto C, Moriwaki Y, Misawa H, Yamashita N, Nagase T, Kawashima K, Yamashita N.
  • Journal Title: Biochem Biophys Res Commun Volume: 438 Issue: 1 Pages: 175-179
  • DOI: 10.1016/j.bbrc.2013.07.048
  • Peer Reviewed
• [Journal Article] FER overexpression is associated with poor postoperative prognosis and cancer-cell survival in non-small cell lung cancer. (2013)
  • Author(s): Kawakami M, Morita S, Sunohara M, Amano Y, Ishikawa R, Watanabe K, Hamano E, Ohishi N, Nakajima J, Yatomi Y, Nagase T, Fukayama M, Takai D.
  • Journal Title: Int J Clin Exp Pathol Volume: 6 Pages: 598-612
  • Peer Reviewed
• [Journal Article] Detection of novel paraja ring finger 2-fer tyrosine kinase mRNA chimeras is associated with poor postoperative prognosis in non-small cell lung cancer. (2013)
  • Author(s): Kawakami M, Ishikawa R, Amano Y, Sunohara M, Watanabe K, Ohishi N, Yatomi Y, Nakajima J, Fukayama M, Nagase T, Takai D.
  • Journal Title: Cancer Sci Volume: 104 Issue: 11 Pages: 1447-1454
  • DOI: 10.1111/cas.12250
  • Peer Reviewed
• [Journal Article] An integrated expression profiling reveals target genes of TGF-β and TNF-α possibly mediated by microRNAs in lung cancer cells (2013)
  • Author(s): Akira Saito, Hiroshi I Iizuka, Masafumi Horie, Mitsuhiro Ohshima, Yasuyuki Morishita, Yoshimitsu Abiko, Takahide Nagase
  • Journal Title: PLoS ONE 8 Volume: 8 Issue: 1 Pages: 158-163
  • DOI: 10.1016/j.bbrc.2012.05.104
  • Peer Reviewed
• [Journal Article] Characterization of human lung cancer-associated fibroblasts in three dimensional in vitro co-culture model (2012)
  • Author(s): Masafumi Horie, Akira Saito, Mitsuhiro Ohshima, Yasuyuki Morishita, Jun Nakajima, Tadashi Kohyama, Takahide Nagase
  • Journal Title: Biochem Biophys Res Commun Volume: 423 Issue: 2 Pages: 158-163
  • DOI: 10.1371/journal.pone.0056587
  • Peer Reviewed
• [Journal Article] Tumor necrosis factor superfamily member LIGHT induces epithelial-mesenchymal transition in A549 human alveolar epithelial cells. (2012)
  • Author(s): Mikami Y
  • Journal Title: Biochem Biophys Res Commun. Volume: 428 Issue: 4 Pages: 451-7
  • DOI: 10.1016/j.bbrc.2012.10.097
  • Peer Reviewed
• [Journal Article] Dynamic change in respiratory resistance during inspiratory and expiratory phases of tidal breathing in patients with chronic obstructive pulmonary disease. (2012)
  • Author(s): Yamauchi Y
  • Journal Title: Int J Chron Obstruct Pulmon Dis. Volume: 7 Pages: 259-69
  • DOI: 10.2147/copd.s30399
  • Peer Reviewed
• [Journal Article] Polymerase reaction without primers throughout for the reconstruction of full-length cDNA from products of rapid amplification of cDNA ends (RACE) (2011)
  • Author(s): Sunohara M, Kawasaki M, Kage H, Watanabe K, Emoto N, Nagase T, Ohishi N, Takai D
  • Journal Title: Biotechnol Lett Volume: 33 Pages: 1301-1307
  • Peer Reviewed
• [Journal Article] Suppression of transforming growth factor β1 in lung alveolar epithelium-decells using adeno-associated virus type 2/5 vectors to carry short hairpin RNA (2011)
  • Author(s): Kage H, Sugimoto K, Sano A, Kitagawa H, Nagase T, Ohishi N, Takai D
  • Journal Title: Exp Lung Res Volume: 37 Pages: 175-185
  • Peer Reviewed
• [Journal Article] Simultaneous stimulation with TGF-β1-and TNF-α induces epithelial mesenchymal transition in bronchial epithelial cells (2011)
  • Author(s): Kamitani S, Yamauchi Y, Kawasaki S, Takami K, Takizawa H, Nagase T, Kohyama T
  • Journal Title: Int Arch Allergy Immnunol Volume: 155 Pages: 119-128
  • Peer Reviewed
• [Presentation] Recent progress of cellular and molecular biology in respiratory diseases (2015)
  • Author(s): Ｎａｇａｓｅ Ｔ
  • Organizer: ＡＰＳＲ ２０１５
  • Place of Presentation: クアラルンプール （マレーシア）
  • Year and Date: 2015-12-04
  • Int'l Joint Research / Invited
• [Presentation] Hot topics in experimental animal model (2014)
  • Author(s): Nagase T
  • Organizer: APSR 2014
  • Place of Presentation: Bali, Indonesia
  • Year and Date: 2014-11-14
  • Invited
• [Presentation] モデルマウスを用いた呼吸器疾患の病態解明 (2013)
  • Author(s): 長瀬隆英
  • Organizer: 第53回日本呼吸器学会総会
  • Place of Presentation: 東京（東京国際フォーラム）
  • Invited
• [Presentation] Cellular and molecular models of lung diseases. (2012)
  • Author(s): Nagase T
  • Organizer: APSR Meeting
  • Place of Presentation: Hong Kong
  • Invited
• [Presentation] Molecular mechanisms underlying respiratory diseases (2011)
  • Author(s): 長瀬隆英
  • Organizer: 16th APSR Meeting
  • Place of Presentation: 上海(中国)(招待講演)
  • Year and Date: 2011-11-06