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Identification of a novel therapeutic target that produces irreversible diabeticg lucotoxicky

Research Project

Project/Area Number 18390100
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pathological medical chemistry
Research InstitutionShiga University of Medical Science

Principal Investigator

KOJIMA Hideto  Shiga University of Medical Science, Faculty of Medicine, Associate Professor (00225434)

Co-Investigator(Kenkyū-buntansha) FUJIMIYA Mineko  Shiga University of Medical Science, Faculty of Medicine, Associate Professor (10199359)
KIMURA Hiroshi  Shiga University of Medical Science, Faculty of Medicine, Professor (00110560)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥16,080,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2007: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2006: ¥11,400,000 (Direct Cost: ¥11,400,000)
Keywordsdiabetic complication / bone marrow / diabetes mellitus / insulin / TNF-α / proinsulin / gene therapy
Research Abstract

Chronic diabetic complications are the major cause of morbidity and mortality among patients with diabetes. We have reported that the fusion of proinsulin-producing (Proins-P) bone-marrow-derived cells (BMDC) with nerve cells underlies diabetic neuropathy in rodents. We also reported that diabetes in mice is associated with the appearance of Proins-P cells in the liver. It was unclear, however, whether these Proins-P BMDC merely transit through the liver or undergo fusion with hepatocytes, normally an extremely rare event. In this study, we found that, in diabetes, BMDC in the liver produce not only Proins but also TNF-a, suggesting that diabetes reprograms gene expression in BMDC, turning on "inappropriate" genes. Bone marrow transplantation using genetically marked donor and recipient mice showed that fusion occurs between Proins-P BMDC and hepatocytes. Cell fusion is further supported by the presence of the Y chromosome in Proins-P cells in female mice that received male bone marrow transplantation cells. Morphologically, Proins-P fusion cells are albumin-producing hepatocytes that constitute 〓2.5% of the liver section area 5 months after diabetes induction. An extensive search failed to reveal any fusion cells in nondiabetic mice. Thus, diabetes causes fusion between Proins-P BMDC and hepatocytes in vivo, an observation that has implications for the pathophysiology of diabetes as well as the fundamental biology of heterotypic cell fusion. To clarify the contribution of TNF-a in Proins-P BMDC on the pathogenesis of diabetic complications, we are generating gene therapeutic vector to suppress TNF-a expression by RNAi. The experiment is ongoing at present, but can show an evidence that the cell fusion have an important roles in the pathogenesis of diabetic complications.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (19 results)

All 2008 2007 2006

All Journal Article (14 results) (of which Peer Reviewed: 5 results) Presentation (2 results) Book (3 results)

  • [Journal Article] Isolation of specific peptides that home to dorsal root ganglion neuronsin mice2008

    • Author(s)
      Oi J, Terashima T, Kojima H, Fujimia M, Maeda K, Arai R, Chan L, Yasuda H, Kashiwagi A, Kimura H
    • Journal Title

      Neuroscience Letters 434

      Pages: 266-272

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] 膵および膵外におけるNgn3とNeuroD1の発現調節と機能2008

    • Author(s)
      小島秀人、木村博
    • Journal Title

      内分泌・糖尿病科 26

      Pages: 141-147

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Isolation of specific peptides that home to dorsal root ganglion neurons in mice2008

    • Author(s)
      Oi, J., Terashima, T., Kojima, H., Fujimia, M., Maeda, K., Arai, R., Chan, L., Yasuda, H., Kashiwagi, A., Kimura, H
    • Journal Title

      Neuroscience Letters 434

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Isolation of specific peptides that home to dorsal root ganglion neuronsin mice2008

    • Author(s)
      Jiro Oi
    • Journal Title

      Neuroscience Letters 434

      Pages: 266-272

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 膵および膵外におけるNgn3とNeuroD1の発現調節と機能2008

    • Author(s)
      小島 秀人
    • Journal Title

      内分泌・糖尿病科 26

      Pages: 141-147

    • Related Report
      2007 Annual Research Report
  • [Journal Article] Aquaporin 7 is a β-cell protein and regulator of intraislet glycerol content and glycerol kinase activity, β-cell mass, and insulin production and secretion2007

    • Author(s)
      Kazuhiro Matsumura
    • Journal Title

      Molecular and Cellular Biology 27

      Pages: 6026-6037

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Fusion of proinsulin-producing bone marrow-derived cells with Hepatocytes in diabetes2007

    • Author(s)
      Fujimiya M, Kojima H, Ichinose M, Arai R, Kimura H, Kashiwagi A, Chan L
    • Journal Title

      Proceedings of National Academy of Science of the United States of America 104

      Pages: 4030-4035

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Fusion of proinsulin-producing bone marrow-derived cells with hepatocytes in diabetes2007

    • Author(s)
      Fujimiya, M., Kojima, H., Ichinose, M., Arai, R., Kimura, H., Kashiwagi, A., Chan, L
    • Journal Title

      Proceedings of National Academy of science of the United States of America 104

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Aquaporin 7 is a β-cell proteinand regulator of intraislet glycerolcontent and glycerol kinaseactivity,β-cell mass,andinsulin production and secretion2007

    • Author(s)
      Kazuhiro Matsumura
    • Journal Title

      Molecular and Cellular Biology 27

      Pages: 6026-6037

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Fusion of proinsulin-producing bone marrow-derived cells with hepatocytes in diabetes.2007

    • Author(s)
      Fujimiya M., Kojima H., Ichinose M.(他4名)
    • Journal Title

      Proc Natl Acad Sci USA. 104(10)

      Pages: 4030-4035

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Extrapancreatic proinsulin/insulin-expressing cells in diabetes mellitus: is history repeating itself?2006

    • Author(s)
      Kojima H, Fujimiya M, Terashima T, Kimura H, ChanL
    • Journal Title

      Endocrine Journal 53

      Pages: 715-722

    • NAID

      10020612249

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] 肝・骨髄幹細胞からの再生2006

    • Author(s)
      小島秀人、木村博、藤宮峯子、柏木厚典
    • Journal Title

      Diabetes Frontier 17

      Pages: 319-323

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Extrapancreatic proinsulin/insulin-expressing cells in diabetes mellitus : Is history repeating itself2006

    • Author(s)
      Kojima, H., Fujimiya, M., Terashima, T., Kimura, H., Chan, L
    • Journal Title

      Endocrine Journal 53

      Pages: 715-722

    • NAID

      10020612249

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Extrapancreatic proinsulin/insulin-expressing cells in diabetes mellitus : is history repeating itself?2006

    • Author(s)
      Kojima H., Fujimiya M., Terashima T.(他2名)
    • Journal Title

      Endocr J. 53(6)

      Pages: 715-722

    • NAID

      10020612249

    • Related Report
      2006 Annual Research Report
  • [Presentation] 脊髄後根神経節ニューロンを標的とするファージ・システムの開発2007

    • Author(s)
      小島秀人、大井二郎、寺島智也、前田健吾、藤宮峯子、新井良八、木村博、柏木厚典、安田斎
    • Organizer
      厚生労働省精神・神経疾患研究委託費、「難治性ニューロパチーの病態に基づく新規治療法の開発」班、分担研究者発表会 平成19年度班会議
    • Place of Presentation
      東京
    • Year and Date
      2007-12-05
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 脊髄後根神経節ニューロンを標的とするファージ・システムの開発2007

    • Author(s)
      小島 秀人
    • Organizer
      厚生労働省精神・神経疾患研究委託費、「難治性ニューロパチーの病態に基づく新規治療法の開発」班、分担研究者発表会平成19年度班会議
    • Place of Presentation
      東京
    • Year and Date
      2007-12-05
    • Related Report
      2007 Annual Research Report
  • [Book] 糖尿病学の進歩20072007

    • Author(s)
      小島秀人、藤宮峯子、柏木厚典、木村博
    • Total Pages
      6
    • Publisher
      診断と治療社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Book] 糖尿病学20072007

    • Author(s)
      小島秀人、寺島智也、藤宮峯子、柏木厚典、木村博
    • Total Pages
      7
    • Publisher
      診断と治療社
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Book] 糖尿病学20072007

    • Author(s)
      小島 秀人
    • Total Pages
      7
    • Publisher
      診断と治療社
    • Related Report
      2007 Annual Research Report

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Published: 2006-04-01   Modified: 2016-04-21  

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