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新たな漫性膵炎モデル:Toll-like receptor3シグナル系を包括するゲノム解析

Research Project

Project/Area Number 15650079
Research Category

Grant-in-Aid for Exploratory Research

Allocation TypeSingle-year Grants
Research Field Laboratory animal science
Research InstitutionEhime University

Principal Investigator

能勢 眞人 (能勢 真人)  愛媛大学, 医学部, 教授 (70030913)

Co-Investigator(Kenkyū-buntansha) 岩崎 美津子  愛媛大学, 医学部, 助手 (00335902)
宮崎 龍彦  愛媛大学, 医学部, 助手 (80239384)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 2004: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2003: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsToll-like receptor 3 / poly I ; C / 慢性膵炎 / 慢性肝内胆管炎 / ゲノム病理学 / 多因子疾患 / poly I : C
Research Abstract

私達は、Toll-like receptor 3 (TLR3)に結合親和性を有するdsRNAウイルスの合成アナログであるpolyinoshinic : polycytidylic acid (poly I : C)を、自己免疫病遺伝的背景をもつMRL系マウスに投与すると、高率に慢性膵炎および原発性胆汁性肝硬変(PBC)に類似した慢性肝内胆管炎を発症することを見いだした。現在までこれらの病変を、高率にしかもTLR3を介する環境要因により発症誘導しうる実験モデルは他になく、多因子疾患をシュミレートする上で貴重であると考えられる。
今年度は種々の系統マウスを用いて、発症機序の解析を行い、以下の成果を得た。
1.慢性膵炎、慢性肝内胆管炎誘導における遺伝的背景:
MRL系マウスのみならず、自己免疫病遺伝的背景をもたない近交系マウス数系統、さらにMRL/1prとC3H/HeJ-1pr/1pr(C3H/1pr)から得られたMXC RI系マウスを用いて、polyI ; C投与を行った。その結果、MRL系と同等の重篤な慢性膵炎のみを発症する系統が存在すること、また、TLR3および関連タンパク質の遺伝子多型についての解析では、少なくともTLR3の遺伝子多型と膵炎、胆管炎の発症との間には関連がないことを明らかにした。
さらに興味深いことに、MXC RI系マウスのなかには、MRL系では見られなかったpolyI ; C投与により糸球体腎炎の増悪する系統が見いだされ、現在、膵炎の責任遺伝子座と共に解析中である。
2.慢性膵炎、慢性肝内胆管炎の病理学特性の解析:
1で見いだされた膵炎好発系の系統において、poly I : C投与で誘導した慢性膵炎の免疫組織学的解析の結果、病変局所への浸潤細胞はMRL系統と同様に、CD4陽性T細胞およびMac2陽性マクロファージであることを明らかにした。

Report

(2 results)
  • 2004 Annual Research Report
  • 2003 Annual Research Report
  • Research Products

    (17 results)

All 2004 Other

All Journal Article (6 results) Publications (11 results)

  • [Journal Article] Endothelial adhesion molecules in glomerular lesions : association with their severity and diversity in lupus models.2004

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

      Kidney Int 65・4

      Pages: 1290-1300

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Nrf2 deficiency improves autoimmune nephritis caused by the fas mutation lpr.2004

    • Author(s)
      Morito N, et al.
    • Journal Title

      Kidney Int 65・5

      Pages: 1703-1713

    • Related Report
      2004 Annual Research Report
  • [Journal Article] High expression of interleukin-1β in the corneal epithelium of MRL/lpr mice is under the control of their genetic background.2004

    • Author(s)
      Okamoto M, et al.
    • Journal Title

      Clin Exp Immunol 136・2

      Pages: 239-244

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Human parvovirus B19 transgenic mice become susceptible to polyarthritis.2004

    • Author(s)
      Takasawa N, et al.
    • Journal Title

      J Immunol 173・7

      Pages: 4675-4683

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Accelerating effect of an MRL gene locus on the severity and onset of arthropathy in DBA/1 mice.

    • Author(s)
      Ohishi H, et al.
    • Journal Title

      Arthritis Rheum (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Antagonist of fractalkine (CX3CL1) ameliorates the initiation and progression of lupus nephritis in MRL/lpr mice.

    • Author(s)
      Inoue A, et al.
    • Journal Title

      Arthritis Rheum (in press)

    • Related Report
      2004 Annual Research Report
  • [Publications] Yamada A, Miyazaki T, Ito MR, Nose M et al.: "Genetic basis of tissue-specificity of vasculitis in MRL/lpr mice."Arthritis Rheum. 48・5. 1445-1451 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Fujii H, Ito MR, Nose M et al.: "Intemalization of antibodies by endothelial cells via fibronectin implicating a novel mechanism in Lupus nephritis."Kidney Int. 64・5. 1662-1670 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ito MR, Nose M, et al.: "Bone marrow transfer of autoimmune diseases in an MRL strain of mice with a deficit in functional Fas ligand : Dissociation of arteritis from glomerulonephritis"Pathol Int. 53・8. 518-524 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hasegawa H, Ito MR, Nose M et al.: "Antagonist of Monocyte Chemoattractant Protein 1 ameliorates the initiation and progression of lupus nephritis and renal vasculitis in MRL/lpr mice."Arthritis Rheum. 48・9. 2555-2566 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sasaki M, Ito MR, et al.: "Antagonist of secondary lymphoid-tissue chemokine (CDR ligand 21) prevents the development of chronic graft-versus-host disease in mice."J Immunol. 170・1. 588-596 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Magoori K, Ito MR. Nose M et al.: "Severe Hypercholesterolemia, impaired fat tolerance and advanced atherosclerosis in mice lacking both LDL receptor-related protein 5 (LRP5) and apolipoprotein"J Biol Chem. 278. 11331-11336 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 能勢眞人: "【血管炎研究がめざす新たな展開】血管炎のゲノミクス"医学のあゆみ. 206・2. 140-142 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 能勢眞人, 宮崎龍彦, 伊藤美津子, 他: "多因子疾患としての新たな自己免疫性膵炎モデルの確立"日本疾患モデル学会記録. 19. 7-13 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 能勢眞人: "ポリジーン疾患としての系統的血管炎-モデルマウスから学ぶもの-"BIO Clinica. 18. 1180-1184 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nakatani K, Ito MR, Nose M et al.: "Endothelial adhesion molecules in glomerular lesions : Association with their severity and diversity in lupus models."Kidney Int. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 伊藤美津子, 能勢眞人(分担執筆): "別冊医学のあゆみ 腎疾患-State of arts 2003-2005"医歯薬出版(株)(東京). 442 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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