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2012 Fiscal Year Final Research Report

Relationship between periodontal disease and systemic diseases: molecular mechanisms and novel therapy discovery

Research Project

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Project/Area Number 22390350
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional basic dentistry
Research InstitutionKyushu University

Principal Investigator

YAMAMOTO Kenji  九州大学, 薬学研究院, 特命教授 (40091326)

Co-Investigator(Kenkyū-buntansha) KAWAKUBO Tomoyo  九州大学, 大学院・薬学研究院, 特任助教 (70507813)
YAMAATAAKE Kumiko  九州大学, 大学院・薬学研究院, 学術研究員 (50622114)
Project Period (FY) 2010 – 2012
Keywords感染症 / 酵素 / 細菌 / 歯学 / 薬学
Research Abstract

To establish the molecular basis of the possible linkage between periodontal diseases and a variety of systemic diseases such as atherosclerosis, obesity, diabetes, and preterm birth and fetal death, we used various animal models and different cell types and manipulated the endolysosomal aspartic proteinase cathepsin E (CatE) as a host-derived protease and gingipains (GP) as a periodontopathogen-derived protease. In this study, we first found that CatE plays a crucial role in host defense against infection with Porphyromonas gingivalis, a major etiological bacterium of adult periodontal disease through proper trafficking and cell surface expressionof Toll-like receptors such as TLR4 in macrophages. Second, GP mediates atherosclerosis progression accelerated by P. gingivalisinfection through selective proteolysis of apolipoprotein B-100 in LDL cholesterol. Third,GP acts as a strong virulence factor to induce preterm birth and low birth weight through the enhancement of immune responses to pregnant mice infected with P. gingivalis. Fourth, CatE plays a crucial role in normal development of adipose tissues through biochemical analysis of CatE-/-mice that were fed a high-fat diet as an obesity mouse model. Forth, using techniques of cDNA display, selection-by-function, γ-ligation-based block shuffling and others, we generated peptide inhibitors for CatE and GP. The newly developed inhibitors for each enzyme showed an IC50 of nM order and high selectivity. This method is thus expected to be widely applicable for the development of peptide inhibitors of various proteases.

  • Research Products

    (21 results)

All 2012 2011 2010

All Journal Article (9 results) (of which Peer Reviewed: 9 results) Presentation (11 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Cathepsin E is critical for the proper trafficking of both intracellular membrane and cell surface proteins2012

    • Author(s)
      Tsukuba T, Okamoto K, Yamamoto K
    • Journal Title

      J. Oral Biosci

      Volume: 54 (1) Pages: 48-53

    • Peer Reviewed
  • [Journal Article] Role of the transcription factor Sp1 in regulating the expression of the murine cathepsin E gene2012

    • Author(s)
      Okamoto K, Okamoto Y, Kawakubo T, Iwata J, Yasuda Y, Tsukuba T, Yamamoto K
    • Journal Title

      J Biochem

      Volume: 151(3) Pages: 263-272

    • Peer Reviewed
  • [Journal Article] Effect of a Japanese energy healing method known as Johrei on viability and proliferation of cultured cancer cells in vitro2012

    • Author(s)
      Abe K, Ichinomiya R, Kanai T, Yamamoto K
    • Journal Title

      J Alternat. Comlement. Med

      Volume: 18(3) Pages: 221-228

    • Peer Reviewed
  • [Journal Article] Emerging roles of cathepsin E in host defense mechanisms2012

    • Author(s)
      Yamamoto K, Kawakubo T, Yasukochi A, Tsukuba T
    • Journal Title

      Biochim. Biophys. Acta

      Volume: 1824 Pages: 105-112

    • Peer Reviewed
  • [Journal Article] The role of cathepsin E in terminal differentiation of keratinocytes2011

    • Author(s)
      Kawakubo T, Yasukochi A, Okamoto K, Okamoto Y, Nakamura S, Yamamoto K
    • Journal Title

      Biol. Chem

      Volume: 392 Pages: 571-583

    • Peer Reviewed
  • [Journal Article] Cathepsin E as a potent anticancer protease2011

    • Author(s)
      Kawakubo T, Yasukochi A, Nakamura S, Yamamoto K
    • Journal Title

      J. Oral Biosci

      Volume: 53 (2) Pages: 126-136

    • Peer Reviewed
  • [Journal Article] Peptide aptamer-based ELISA-like system for detection of cathepsin E in tissues and plasma2011

    • Author(s)
      Kitamura K, Biyani M, Futakami M, Ueno-Tsuji S, Suzuki M, Kawakubo T, Yamamoto K, Nishigaki K
    • Journal Title

      J. Mol. Biomark. Diagn

      Volume: 2 Pages: 104

    • DOI

      10.4172/2155-9929.1000104

    • Peer Reviewed
  • [Journal Article] In vitro selection of cathepsin E-activity-enhancing peptide aptamers at neutral pH2011

    • Author(s)
      Biyani M, Futakami M, Kitamura K, Kawakubo T, Suzuki M, Yamamoto K, Nishigaki K
    • Journal Title

      Int. J. Pep

    • DOI

      DOI:10.1155/2011/834525

    • Peer Reviewed
  • [Journal Article] Cathepsin E enhances anticancer activity of doxorubicin on human prostate cancer cells showing resistance to TRAIL-mediated apoptosis2010

    • Author(s)
      Yasukouchi A, Kawakubo T, Nakamura S, Yamamoto K
    • Journal Title

      Biol. Chem

      Volume: 391 Pages: 947-958

    • Peer Reviewed
  • [Presentation] Cathepsin E: related signaling systems, functions and implication in diseases2012

    • Author(s)
      Yamamoto K, Kawakubo T, Yasukochi A, Okamoto K, Tsukuba T
    • Organizer
      13th International Symposium on Proteinase Inhibitors and Biological Control
    • Place of Presentation
      Portoroz, Slovenia
    • Year and Date
      20120922-26
  • [Presentation] p53 はカテプシン E 遺伝子の発現を制御する2012

    • Author(s)
      岡元邦彰、岩田淳一、坂井詠子、西下一久、山本健二、筑波隆幸
    • Organizer
      第85回日本生化学会年会
    • Place of Presentation
      福岡
    • Year and Date
      2012-12-15
  • [Presentation] Selection-by-Function 法によるプロテアーゼアクチベーターの開発2012

    • Author(s)
      小松将之、北村幸一郎、Sunita Gautam, Madhu Biyani, 山本健二、西垣功一
    • Organizer
      第17回日本病態プロテアーゼ学会
    • Place of Presentation
      浜松
    • Year and Date
      2012-08-10
  • [Presentation] 反復流産病態における妊娠初期脱落膜中マクロファージの cathepsin E の役割2012

    • Author(s)
      後藤志信、尾崎康彦、都筑佳苗、安河内篤、川久保友世、国松己歳、山本健二、杉浦真弓
    • Organizer
      第17回日本病態プロテアーゼ学会
    • Place of Presentation
      浜松
    • Year and Date
      2012-08-10
  • [Presentation] Accumulation of NADPH oxidase (NOX2) and increased oxidative stress in cathepsin E-deficient macrophages2012

    • Author(s)
      Tsukuba T, Kadowaki T, Okamoto K, Yamamoto K
    • Organizer
      The 85^<th>Annual Meeting of Pharmacological Society
    • Place of Presentation
      Kyoto
    • Year and Date
      2012-03-16
  • [Presentation] Idetification of two transcripts and in vivo promoter analysis for cathepsin E2012

    • Author(s)
      Okamoto K, Sakai E, Nishishita K, Yamamoto K, Tsukuba T
    • Organizer
      The 85^<th>Annual Meeting of Pharmacological Society
    • Place of Presentation
      Kyoto
    • Year and Date
      2012-03-16
  • [Presentation] Cathepsin E-induced growth arrest and apoptosis of cancer cells and the related signaling2012

    • Author(s)
      Yamamoto K, Kawakubo T, Yasukochi A, Tsukuba T.
    • Organizer
      The 85^<th> Annual Meeting of Pharmacological Society
    • Place of Presentation
      Kyoto
    • Year and Date
      2012-03-14
  • [Presentation] Novel functions of cathepsin E in epidermal differentiation and aging2010

    • Author(s)
      Yamamoto K
    • Organizer
      12th International Symposium on Proteinase Inhibitors and Biological Control
    • Place of Presentation
      Portoroz, Slovenis
    • Year and Date
      20100925-29
  • [Presentation] Cathepsin E is essential for proper mammogenesis2010

    • Author(s)
      Kawakubo T, Yasukochi A, Yamamoto K
    • Organizer
      12th Symposium on Proteases, Inhibitors and Biological Control
    • Place of Presentation
      Portoroz (Slovenia)
    • Year and Date
      2010-09-25
  • [Presentation] Analysis of cathepsin E function in epidermal differentiation using a model of DMBA/TPA- induced skin papillomas2010

    • Author(s)
      Yasukochi A, Kawakubo T, Yamamoto K
    • Organizer
      12th Symposium on Proteases, Inhibitors and Biological Control
    • Place of Presentation
      Portoroz (Slovenia)
    • Year and Date
      2010-09-25
  • [Presentation] Cathepsin E: related signaling systems, functions and implication in diseases2010

    • Author(s)
      Yamamoto K, Kawakubo T, Yasukochi A, Okamoto K, Tsukuba T
    • Organizer
      13th International Symposium on Proteinase Inhibitors and Biological Control
    • Place of Presentation
      Portoroz, Slovenis
    • Year and Date
      2010-09-24
  • [Patent(Industrial Property Rights)] カテプシン E の腫瘍マーカーとしての用途およびカテプシン E ならびにカテプシン D の腫瘍血管新生阻害療法としての用途2010

    • Inventor(s)
      山本健二、岩田淳一
    • Industrial Property Rights Holder
      山本健二、岩田淳一
    • Industrial Property Number
      特許第4452791 号
    • Acquisition Date
      2010-02-12

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Published: 2014-08-29   Modified: 2023-03-16  

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