国際共同研究による間質性肺炎の新規バイオマーカーの開発と創薬の試み

• Project/Area Number: 25253057
• 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: Hiroshima University
• Principal Investigator: 河野 修興 広島大学, 医歯薬保健学研究院(医), 教授 (80215194)
• Co-Investigator(Kenkyū-buntansha): 服部 登 広島大学, 医歯薬保健学研究院(医), 准教授 (00283169) ; 横山 彰仁 高知大学, 教育研究部医療学系臨床医学部門, 教授 (30191513) ; 粟井 和夫 広島大学, 医歯薬保健学研究院(医), 教授 (30294573) ; 大下 慎一郎 広島大学, 病院(医), 講師 (50508132) ; 岩本 博志 広島大学, 病院(医), 講師 (60457398) ; 中島 拓 広島大学, 病院(医), 病院助教 (90643792) ; 石川 暢久 広島大学, 大学院医歯薬保健学研究院, 講師 (90423368)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Declined (Fiscal Year 2016)
• Budget Amount: ¥33,150,000 (Direct Cost: ¥25,500,000、Indirect Cost: ¥7,650,000); Fiscal Year 2016: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000); Fiscal Year 2015: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000); Fiscal Year 2014: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000); Fiscal Year 2013: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000)
• Keywords: 間質性肺炎 / バイオマーカー / SNP / 人種差 / 分子標的治療薬 / マイクロアレイ

Outline of Annual Research Achievements

(1)マイクロアレイ解析から同定した新規血清バイオマーカー・創薬の候補分子のスクリーニング：特発性間質性肺炎（IIP）患者の肺組織と健常肺組織のマイクロアレイ解析により、IIP肺では細胞間の相互作用および接着に関わる分子（DSG3, PCDHGA9, DDR1, MUC1)や細胞増殖に関わる分子（CDC25C, GFI1B)などが高発現していた。Pathway解析をおこないIIP肺においては細胞増殖関連の経路が亢進していることを示した。免疫組織染色をおこない、同定したバイオマーカー候補分子がIIP肺組織において高発現していることを確認した。
(2)間質性肺炎の新規血清バイオマーカーの開発：新規バイオマーカー候補分子であるMMP-7とCCL18のIPFの血中バイオマーカーとしての有用性を検討した。MMP-7はKL-6と共に診断能、予後予測能に優れていることが示された。一方でCCL18は細菌性肺炎患者における疑陽性の問題点が明らかとなった。予後予測能の検討では、MMP-7とKL-6を組み合わせて使用することが有効である可能性を示した。
(3)間質性肺炎の病態ならびに人種的な相違解明：日独のIPF患者における急性増悪の頻度の比較検討をおこなった。日本人IPF患者ではドイツ人と比較して急性増悪の頻度が高率であった。急性増悪と関連する背景因子の多変量解析をおこなったところ、人種差が独立した因子であることが示された。現在、日独のIPF患者のHRCT所見を両国の医師によって定量化する作業を進めており、この作業が終了次第、急性増悪と画像所見との関連についても検討する予定である。
遺伝子多型の比較検討においてはFAM13Aの遺伝子多型は日本人コホートではIPF患者において健常者と比較して有意に高率であり、更に同遺伝子多型は急性増悪のリスク因子かつ予後不良因子であった。

Research Progress Status

翌年度、交付申請を辞退するため、記入しない。

Strategy for Future Research Activity

翌年度、交付申請を辞退するため、記入しない。

Research Products

• [Journal Article] Long-term pulmonary complications of chemical weapons exposure in former poison gas factory workers. (2016)
  • Author(s): Nishimura Y, Iwamoto H, Ishikawa N, Hattori N, Horimasu Y, Ohshimo S, Kohno N.
  • Journal Title: Inhal Toxicol Volume: 28 Issue: 8 Pages: 1-6
  • DOI: 10.3109/08958378.2016.1173133
  • Peer Reviewed
• [Journal Article] Comparative Study of Circulating MMP-7, CCL18, KL-6, SP-A, and SP-D as Disease Markers of Idiopathic Pulmonary Fibrosis (2016)
  • Author(s): Kosuke Hamai, Hiroshi Iwamoto*, Nobuhisa Ishikawa, Yasushi Horimasu, Takeshi Masuda, Shintaro Miyamoto, Taku Nakashima, Shinichiro Ohshimo, Kaznounori Fujitaka, Hironobu Hamada , Noboru Hattori, Nobuoki Kohno
  • Journal Title: Disease markers Volume: in press
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] MT95-4, a fully humanized antibody raised against aminopeptidase N, reduces tumor progression in a mouse model. (2015)
  • Author(s): Akita S, Hattori N, Masuda T, Horimasu Y, Nakashima T, Iwamoto H, Fujitaka K, Miyake M, Kohno N
  • Journal Title: Cancer science Volume: 106 Issue: 7 Pages: 921-928
  • DOI: 10.1111/cas.12692
  • Peer Reviewed / Open Access
• [Journal Article] Histological Quantification of Gene Silencing by Intratracheal Administration of Dry Powdered Small-Interfering RNA/Chitosan Complexes in the Murine Lung. (2015)
  • Author(s): Ihara D, Hattori N, Horimasu Y, Masuda T, Nakashima T, Senoo T, Iwamoto H, Fujitaka K, Okamoto H, Kohno N
  • Journal Title: Pharmaceutical research Volume: 32 Issue: 12 Pages: 3877-3885
  • DOI: 10.1007/s11095-015-1747-6
  • Peer Reviewed / Open Access
• [Journal Article] Effect of increasing respiratory rate on airway resistance and reactance in COPD patients. (2015)
  • Author(s): Nakagawa M, Hattori N, Haruta Y, Sugiyama A, Iwamoto H, Ishikawa N, Fujitaka K, Murai H, Tanaka J, Kohno N.
  • Journal Title: Respirology Volume: 20 Issue: 1 Pages: 87-94
  • DOI: 10.1111/resp.12387
  • Peer Reviewed / Open Access
• [Journal Article] Airway inflammation in Japanese COPD patients compared with smoking and nonsmoking controls. (2015)
  • Author(s): Nobuhisa Ishikawa,1 Noboru Hattori,2 Nobuoki Kohno, Akihiro Kobayashi, Tomoyuki Hayamizu, Malcolm Johnson
  • Journal Title: Int J Chron Obstruct Pulmon Dis. Volume: 10 Pages: 185-92
  • DOI: 10.2147/copd.s74557
  • NAID: 120006799350
  • Peer Reviewed / Open Access
• [Journal Article] MUC5B promoter polymorphism in Japanese patients with idiopathic pulmonary fibrosis. (2015)
  • Author(s): Horimasu Y, Ohshimo S, Bonella F, Tanaka S, Ishikawa N, Hattori N, Kohno N, Guzman J, Costabel U.
  • Journal Title: Respirology. Volume: 20 Issue: 3 Pages: 439-44
  • DOI: 10.1111/resp.12466
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A pilot study: a combined therapy using polymyxin-B hemoperfusion and extracorporeal membrane oxygenation for acute exacerbation of interstitial pneumonia. (2015)
  • Author(s): Itai J, Ohshimo S, Kida Y, Ota K, Iwasaki Y, Hirohashi N, Bonella F, Guzman J, Costabel U, Kohno N, Tanigawa K.
  • Journal Title: Sarcoidosis Vasc Diffuse Lung Dis Volume: 31 Pages: 343-349
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Differences in serum SP-D levels between German and Japanese subjects are associated with SFTPD gene polymorphisms. (2014)
  • Author(s): Horimasu Y, Hattori N, Ishikawa N, Tanaka S, Bonella F, Ohshimo S, Guzman J, Costabel U, Kohno N
  • Journal Title: BMC Med Genet Volume: 15 Issue: 1 Pages: 4-4
  • DOI: 10.1186/1471-2350-15-4
  • NAID: 120006799353
  • Peer Reviewed / Open Access
• [Journal Article] Baseline KL-6 predicts increased risk for acute exacerbation of idiopathic pulmonary fibrosis (2014)
  • Author(s): Ohshimo S, Ishikawa N, Horimasu Y, Hattori N, Hirohashi N, Tanigawa K, Kohno N, Bonella F, Guzman J, Costabel U
  • Journal Title: Respir Med. Volume: 108 Issue: 7 Pages: 1031-9
  • DOI: 10.1016/j.rmed.2014.04.009
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SK-216, an inhibitor of plasminogen activator inhibitor-1, limits tumor progression and angiogenesis. (2013)
  • Author(s): Masuda T, Hattori N, Senoo T, Akita S, Ishikawa N, Fujitaka K, Haruta Y, Murai H, Kohno N.
  • Journal Title: Mol Cancer Ther Volume: 12 Issue: 11 Pages: 2378-88
  • DOI: 10.1158/1535-7163.mct-13-0041
  • Peer Reviewed
• [Journal Article] Characteristics of inspiratory and expiratory reactance in interstitial lung disease. (2013)
  • Author(s): Sugiyama A, Hattori N, Haruta Y, Nakamura I, Nakagawa M, Miyamoto S, Onari Y, Iwamoto H, Ishikawa N, Fujitaka K, Murai H, Kohno N.
  • Journal Title: Respir Med Volume: 107 Issue: 6 Pages: 875-82
  • DOI: 10.1016/j.rmed.2013.03.005
  • Peer Reviewed
• [Journal Article] A nationwide epidemiological survey of chronic hypersensitivity pneumonitis in Japan. (2013)
  • Author(s): Okamoto T, Miyazaki Y, Ogura T, Chida K, Kohno N, Kohno S, Taniguchi H, Akagawa S, Mochizuki Y, Yamauchi K, Takahashi H, Johkoh T, Homma S, Kishi K, Ikushima S, Konno S, Mishima M, Ohta K, Nishioka Y, Yoshimura N, Munakata M, Watanabe K, Miyashita Y, Inase N.
  • Journal Title: Respir Investig Volume: 51 Pages: 191-199
  • Peer Reviewed
• [Journal Article] RASEF is a novel diagnostic biomarker and a therapeutic target for lung cancer. (2013)
  • Author(s): Oshita H, Nishino R, Takano A, Fujitomo T, Aragaki M, Kato T, Akiyama H, Tsuchiya E, Kohno N, Nakamura Y, Daigo Y.
  • Journal Title: Mol Cancer Res Volume: 11 Issue: 8 Pages: 937-951
  • DOI: 10.1158/1541-7786.mcr-12-0685-t
  • Peer Reviewed
• [Journal Article] Cross-sectional and prospective study of the association between lung function and prediabetes (2013)
  • Author(s): Yamane T, Yokoyama A, Kitahara Y*, Miyamoto S, Haruta Y, Hattori N, Yamane K, Hara H, Kohno N
  • Journal Title: BMJ Open Volume: 3 Issue: 2 Pages: 3-3
  • DOI: 10.1136/bmjopen-2012-002179
  • NAID: 120006799354
  • Peer Reviewed
• [Presentation] MUC1 gene polymorphism and serum KL-6 in lung adenocarcinoma. (2015)
  • Author(s): Horimasu Y, Ishikawa N, Tanaka S, Iwamoto H, Ohshimo S, Fujitaka K, Hattori N, Hamada H, Kohno N.
  • Organizer: European Respiratory Society International Congress 2015
  • Place of Presentation: アムステルダム（オランダ）
  • Year and Date: 2015-09-26
  • Int'l Joint Research
• [Presentation] Comparative analysis of multiple gene polymorphisms for acute exacerbation of idiopathic pulmonary fibrosis. (2015)
  • Author(s): Ohshimo S, Yamaoka C, Horimasu Y, Iwamoto H, Fujitaka K, Hamada H, Hattori N, Hirohashi N, Tanigawa K, Bonella F, Guzman J, Costabel U, Kohno N.
  • Organizer: European Respiratory Society International Congress 2015
  • Place of Presentation: アムステルダム（オランダ）
  • Year and Date: 2015-09-26
  • Int'l Joint Research
• [Presentation] 日本人の間質性肺炎急性増悪症例における体外式膜型人工肺（ECMO）の有用性 (2015)
  • Author(s): 大下慎一郎, 木田佳子, 太田浩平, 京道人, 島谷竜俊, 儀賀普嗣, 小山和宏, 稲川嵩紘, 鈴木慶, 山賀聡之, 田邉優子, 大谷直嗣, 貞森拓磨, 宇根一暢, 津村龍, 岩崎泰昌, 廣橋伸之, 服部登, 河野修興, 谷川攻一
  • Organizer: 第37回日本呼吸療法医学会総会
  • Place of Presentation: 国立京都国際会館館（京都）
  • Year and Date: 2015-07-17
• [Presentation] Growth differentiation factor-15 (GDF-15) as prognostic factor in German patients with idiopathic pulmonary fibrosis. (2015)
  • Author(s): Ohshimo S, Hamai K, Bonella F, Yamaoka C, Horimasu Y, Iwamoto H, Ishikawa N, Fujitaka K, Murai H, Hamada H, Hattori N, Hirohashi N, Tanigawa K, Guzman J, Costabel U, Kohno N.
  • Organizer: American Thoracic Society International Conference 2015
  • Place of Presentation: デンバー（アメリカ合衆国）
  • Year and Date: 2015-05-17
  • Int'l Joint Research
• [Presentation] HRCT Findings as a Predictive Factor for Acute Exacerbation of Idiopathic Pulmonary Fibrosis. (2015)
  • Author(s): Yamaoka C, Horimasu Y, Iwamoto H, Ohshimo S, Fujitaka K, Murai H, Hattori N, Hamada H, Kohno N.
  • 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）
  • Year and Date: 2015-04-17
• [Presentation] 特発性肺線維症における血清バイオマーカーの意義に関する検討 (2015)
  • Author(s): 濵井宏介、岩本博志、石川暢久、大下慎一郎、濱田泰伸、堀益靖、藤高一慶、村井博、服部登、河野修興
  • 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）
  • Year and Date: 2015-04-17
• [Presentation] 放射線肺線維症マウスモデルにおける肺の線維化とPAI-1(plasminogen activator inhibitor-1)の関与についての検討 (2015)
  • Author(s): 塩谷咲千子、服部登、平野有美、妹尾直、益田武、堀益靖、中島拓、岩本博志、藤高一慶、河野修興
  • 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）
  • Year and Date: 2015-04-17
• [Presentation] Growth differentiation factor-15 (GDF-15) as prognostic factor in Caucasians with idiopathic pulmonary fibrosis. (2015)
  • Author(s): Ohshimo S, Hamai K, Bonella F, Yamaoka C, Horimasu Y, Iwamoto H, Ishikawa N, Fujitaka K, Murai H, Hamada H, Hattori N, Hirohashi N, Tanigawa K, Guzman J, Costabel U, Kohno N.
  • 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）
  • Year and Date: 2015-04-17
• [Presentation] 13.Angiopoietin-2 Gene Polymorphism as Prognostic Factor in Caucasians with Idiopathic Pulmonary Fibrosis (2014)
  • Author(s): Ohshimo S, Horimasu Y, Bonella F, Iwamoto H, Ishikawa N, Fujitaka K, Haruta Y, Murai H, Hattori N, Hirohashi N, Tanigawa K, Guzman J, Costabel U, Kohno N
  • Organizer: European Respiratory Society Annual Congress
  • Place of Presentation: Munich, Germany
  • Year and Date: 2014-09-06 – 2014-09-10
• [Presentation] 1.Gene expression profiles of idiopathic interstitial pneumonias: Molecular signatures of pulmonary fibrosis (2014)
  • Author(s): Ishikawa N, Masuda T, Horimasu Y, Hattori N, Ohshimo S, Kohno N
  • Organizer: American Thoracic society international Conference
  • Place of Presentation: San Diego, USA
  • Year and Date: 2014-05-16 – 2014-05-21
• [Presentation] 2.Impact of Ethnic Difference and TERT Gene Polymorphisms in the Acute Exacerbation of Idiopathic Pulmonary Fibrosis (2014)
  • Author(s): Ohshimo S, Ishikawa N, Horimasu Y, Fujitaka K, Haruta Y, Murai H, Hattori N, Bonella F, Guzman J, Costabel U, Kohno N
  • Organizer: American Thoracic society international Conference
  • Place of Presentation: San Diego, USA
  • Year and Date: 2014-05-16 – 2014-05-21
• [Presentation] 3.Annual decline in lung function can predict the prognosis of patients with chronic hypersensitivity pneumonia (2014)
  • Author(s): Horimasu Y, Ishikawa N, Nakashima T, Iwamoto H, Senoo T, Ohshimo S, Fujitaka K, Haruta Y, Murai H, Hattori N, Kohno N
  • Organizer: American Thoracic society international Conference
  • Place of Presentation: San Diego, USA
  • Year and Date: 2014-05-16 – 2014-05-21
• [Presentation] 1.Bronchoalveolar lavage cellular pattern can predict the prognosis of patients with chronic hypersensitivity pneumonia (2014)
  • Author(s): Horimasu Y, Ishikawa N, Nakashima T, Senoo T, Ohshimo S, Fujitaka K, Haruta Y, Murai H, Hattori N, Kohno N
  • Organizer: 第54回日本呼吸器学会学術講演会
  • Place of Presentation: 大阪
  • Year and Date: 2014-04-25 – 2014-04-27
• [Presentation] Discovery and clinical application of KL-6, a circulating biomarker for interstitial lung diseases (2013)
  • Author(s): Kohno N
  • Organizer: European Respiratory Society Annual Congress
  • Place of Presentation: バルセロナ、スペイン
  • Invited
• [Presentation] Gene expression profiles of chronic hypersensitivity pneumonitis: Molecular signatures of pulmonary fibrosis. (2013)
  • Author(s): Ishikawa N, Taniwaki M, Horimasu Y, Iwamoto H, Ohshimo S, Fujitaka K, Haruta Y, Murai H, Hattori N, Kohno N.
  • Organizer: American Thoracic society international Conference 2013
  • Place of Presentation: フィラデルフィア、アメリカ
• [Presentation] 3. Ethnic difference in the incidence of acute exacerbation in idiopathic pulmonary fibrosis. (2013)
  • Author(s): Ohshimo S, Ishikawa N, Horimasu Y, Fujitaka K, Haruta Y, Murai H, Hattori N, Bonella F, Kohno N, Guzman J, Costabel U.
  • Organizer: American Thoracic society international Conference 2013
  • Place of Presentation: フィラデルフィア、アメリカ
• [Presentation] Difference of serum SP-D levels between German and Japanese are associated with SFTP gene polymorphisms. (2013)
  • Author(s): Horimasu Y, Hattori N, Ishikawa N, Tanaka S, Bonella F, Ohshimo S, Guzman J, Costabel U, KohnoN.
  • Organizer: American Thoracic society international Conference 2013
  • Place of Presentation: フィラデルフィア、アメリカ
• [Presentation] 4. KL-6, SP-D and MMP-7 as serum biomarkers for early detection of interstitial lung diseases. (2013)
  • Author(s): Ishikawa N, Yoshioka K, Horimasu Y, Iwamoto H, Ohshimo S, Hattori N, Kohno N.
  • Organizer: 2013 European Respiratory Society Annual Congress
  • Place of Presentation: バルセロナ、スペイン
• [Presentation] MUC1 gene polymorphisms are associated with serum KL-6 levels and pulmonary dysfunction in pulmonary alveolar proteinosis. (2013)
  • Author(s): Ohshimo S, Horimasu Y, Bonella F, Ishikawa N, Fujitaka K, Haruta Y, Murai H, Hirohashi N, Hattori N, Tanigawa K, KohnoN, Guzman J, Costabel U.
  • Organizer: 2013 European Respiratory Society Annual Congress
  • Place of Presentation: バルセロナ、スペイン