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Airway Inflammation due to the Mutated CFTR and Modulation with Macrolide Antibiotics

Research Project

Project/Area Number 13670619
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Respiratory organ internal medicine
Research InstitutionOkinaka Memorial Institute for Medical Research (2003)
Jikei University School of Medicine (2001-2002)

Principal Investigator

YOSHIMURA Kunihiko  Okinaka Memorial Institute for Medical Research, Researcher, 研究員 (60246452)

Co-Investigator(Kenkyū-buntansha) AKOI Kaoru  Jikei University, School of Medicine, Assistant Professor, 医学部, 講師 (90212357)
GHANSHYAM D.Heda  米国Tennessee大学, 健康科学センター, 講師
HEDA Ghanshyam D.  Tennessee University, Health Science Center, Assistant Professor
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2002: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsCFTR / macrolides / gene mutations / diffuse panbronchiolitis / ΔF508 / cystic fibrosis / mutagenesis / gene expression
Research Abstract

Diffuse panbronchiolitis(DPB), a chronic inflammatory airway disease affecting mainly adults in Asian countries such as Japan, presents characteristic pulmonary manifestations similar to those of cystic fibrosis(CF). Since the introduction of macrolide antibiotics(MA) such as erythromycin and clarithromycin to treat patients with DPB has successfully and dramatically improved the prognosis of the disease, and our previous studies demonstrated a high prevalence of CFTR gene mutations in those patients with DPB, we have hypothesized that CFTR might be responsible, at least in part, for the pathogenesis of DPB, and the expression of CFTR could be modulated with MA as well. First, we have analyzed possible modulation of CFTR mRNA expression and splicing of CFTR exon 9 with MA. Interestingly, MA did not alter the levels of CFTR mRNA, but the amounts of exon 9-CFTR mRNA increased in a dose-dependent manner, suggesting the likely negative modulation of functional CFTR mRNA. In terms of CFTR channel property, LLCPK and LLCPKΔF508, which were stably transformed cell lines with normal CFTR cDNA and mutated CFTRΔF508, were utilized for in vitro chloride efflux assay. It seemed that MA could upregulate the function of CFTR channel activity. Next, we have continued to evaluate the CFTR genotypes in Japanese patients with CF, DPB and congenital bilateral absence of vas deferens. Through the study, we have found multiple rare or unique mutations which have not been deposited to the world-wide CF Mutation Database. Finally, the functional properties of the mutations detected in Japanese individuals such as 125C and Q1352H have been conducted by constructing expression plasmid vectors driven by Rous sarcoma virus promoter and stably transfecting those plasmids into CFTR-non-producing cells. The experiments and analyses are currently underway.

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (28 results)

All 2003 2002 Other

All Journal Article (10 results) Book (1 results) Publications (17 results)

  • [Journal Article] 日本人cystic fibrosis患者におけるCFTR遺伝子変異解析2003

    • Author(s)
      吉村邦彦
    • Journal Title

      厚生労働省特定疾患対策研究事業「難治性膵疾患に関する調査研究班」平成14年度研究報告書

      Pages: 213-216

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] CFTRに対するマクロライドの作用の分子生物学的検討2003

    • Author(s)
      吉村邦彦, ほか
    • Journal Title

      Jpn J Antibiotics 56-suppl

      Pages: 117-120

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] High prevalence of mutations of the CFTR gene in Japanese individuals with congenital bilateral absence of the vas deferens2003

    • Author(s)
      Anzai C, Yoshimura K, et al.
    • Journal Title

      J Cystic Fibrosis 2-1

      Pages: 14-18

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Molecular mechanisms of effects of macrolide antibiotics on CFTR (in Japanese)2003

    • Author(s)
      Yoshimura K et al.
    • Journal Title

      Jpn J Antibiotics 56

      Pages: 117-120

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] High prevalence of mutations of the CFTR gene in Japanese individuals with congenital bilateral absence of the vas deferens2003

    • Author(s)
      Anzai C et al.
    • Journal Title

      J Cystic Fibrosis 2

      Pages: 14-18

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] DPBの治療反応性とCFTR遺伝子変異2002

    • Author(s)
      吉村邦彦
    • Journal Title

      Therapeutic Research 23-9

      Pages: 1825-1828

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] わが国の嚢胞性線維症におけるCFTR遺伝子の解析2002

    • Author(s)
      吉村邦彦, ほか
    • Journal Title

      厚生労働省特定疾患対策研究事業「難治性膵疾患に関する調査研究班」平成13年度研究報告書

      Pages: 111-116

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Expression of progastrin-releasing peptide and gastrin-releasing peptide receptor mRNA transcripts in tumor cells in patients with small cell lung cancer2002

    • Author(s)
      Uchida K, et al.
    • Journal Title

      J Cancer Res Clin Oncol 128

      Pages: 633-640

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] CFTR gene mutations and modulation with macrolide antibiotics (in Japanese)2002

    • Author(s)
      Yoshimura K
    • Journal Title

      Therapeutic Research 23

      Pages: 1825-1828

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Expression of progastrin-releasing peptide and gastrin-releasing peptide receptor mRNA transcripts in tumor cells from patients with small cell lung cancer2002

    • Author(s)
      Uchida K et al.
    • Journal Title

      J Cancer Res Clin Oncol 128

      Pages: 633-640

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Book] Annual Review 2003呼吸器:日本人におけるCFTRの遺伝子多型(工藤翔二, 土屋了介, 金澤 実, 太田 健編)2003

    • Author(s)
      吉村邦彦
    • Publisher
      中外医学社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] 吉田邦彦: "DPBの治療反応性とCFTR遺伝子変異"Therapeutic Research. 23-9. 1825-1828 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] 吉村邦彦ほか: "わが国の嚢胞性線維症におけるCFTR遺伝子の解析"厚生労働省特定疾患対策研究事業「難治性膵疾患に関する調査研究班」平成13年度研究報告書. 111-116 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] Uchida K, et al.: "Expression of progastrin-releasing peptide and gastrin-releasing peptide receptor mRNA transcripts in tumor cells in patients with small cell lung cancer"J Cancer Res Clin Oncol. 128. 633-640 (2002)

    • Related Report
      2003 Annual Research Report
  • [Publications] 吉村邦彦: "日本人cystic fibrosis患者におけるCFTR遺伝子変異解析"厚生労働省特定疾患対策研究事業「難治性膵疾患に関する調査研究班」平成14年度研究報告書. 213-216 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 吉村邦彦, ほか: "CFTRに対するマクロライドの作用の分子生物学的検討"Jpn J Antibiotics. 56-suppl. 117-120 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Anzai C, Yoshimura K, et al.: "High prevalence of mutations of the CFTR gene in Japanese individuals with congenital bilateral absence of the vas deferens"J Cystic Fibrosis. 2-1. 14-18 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 吉村邦彦: "Annual Review 2003呼吸器:日本人におけるCFTRの遺伝子多型(工藤翔二, 土屋了介, 金澤 実, 太田健編)"中外医学社. 128-136 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 吉村邦彦, 西森功, 衛藤義勝, 田代征記, 山城雄一郎, 小川道雄: "わが国の嚢胞性線維症におけるCFTR遺伝子の解析"厚生労働省特定疾患対策研究事業「難治性膵疾患に関する調査研究班」平成13年度研究報告書. 111-116 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 吉村邦彦: "DPBの治療反応性とCFTR遺伝子変異"Therapeutic Research. 23-9. 1825-1828 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Anzai C, Yoshimura K, Morokawa N, Okada H, Kamidono S, Eto Y: "High prevalence of mutations of the CFTR gene in Japanese individuals with congenital bilateral absence of the vas deferens"J Cystic Fibrosis. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 吉村邦彦, 衛藤義勝: "日本人cystic fibrosis患者のCFTR遺伝子変異解析"厚生労働省特定疾患対策研究事業 「難治性膵疾患に関する調査研究班」 平成12年度研究報告書. 245-250 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 吉村邦彦, ほか: "嚢胞性線維症におけるCFTR遺伝子の解析"厚生労働省特定疾患対策研究事業 「難治性膵疾患に関する調査研究班」 平成12年度研究報告書. 96-100 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 吉村邦彦, ほか: "DPBとして加療され経過中に呼吸不全にて死亡したcystic fibrosisの1例"Therapeutic Research. 21-8. 1876-1878 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 青木 薫, 吉村邦彦: "喫煙感受性遺伝子と呼吸器疾患"呼吸. 20-10. 952-959 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 吉村邦彦: "呼吸器疾患関連遺伝子異常-日本におけるCFの現状-"分子呼吸器病. 5-3. 244-250 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 吉村邦彦: "単遺伝子性遺伝性疾患:嚢胞性線維症"日本胸部臨床. 60-増刊号. S161-169 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 吉村邦彦: "遺伝子検査早わかり事典:嚢胞性線維症 (cystic fibrosis, CF)"中井利昭ら編, 中外医学社. 99 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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