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Elucidation of aging mechanism of hyaluronan knock-down mouse and its application to the evaluation for effect of anti-aging reagents

Research Project

Project/Area Number 20300225
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Applied health science
Research InstitutionAomori University of Health and Welfare

Principal Investigator

KON Atsushi  青森県立保健大学, 健康科学部, 教授 (60271798)

Co-Investigator(Kenkyū-buntansha) SAWAMURA Daisuke  弘前大学, 大学院・医学研究科, 教授 (60196334)
Project Period (FY) 2008 – 2011
Project Status Completed (Fiscal Year 2011)
Budget Amount *help
¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000)
Fiscal Year 2011: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2010: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2009: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2008: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Keywordsヒアルロン酸 / 糖鎖 / アンチエイジング / 老化 / 発現制御
Research Abstract

Hyaluronan(HA), a non-sulfated glycosaminoglycan of high molecular mass, presents in various tissues as a major component of the extracellular matrix and plays an important role in regeneration, wound healing, and anti-aging of organs. We have previously reported that 4-methylumbelliferone(MU) specifically inhibits HA synthesis. In this study, we first investigated the expression of HA-related gene, such as HA synthase(HAS-1, HAS-2, HAS-3), hyaluronidase(Hyal-1, Hyal-2, Hyal-3, Hyal-4), and HA receptor(CD44, RHAMM). We have demonstrated that HAS-2 gene transcription in both epidermis and dermis, and RHAMM transcription in epidermis were reduced in HA-knock-down mice. These data suggested that MU treatment specifically downregulates gene expressions of HAS-2 and RHAMM induced the HA production, resulting in skin aging, such as wrinkle formation and skin dehydration in HA knockdown mice. Next, we have detected sixty one kinds of HA knock-down mice specific genes by using DNA microarray a … More nalysis. Specifically, toll-like receptor 3 gene was strongly down-regulated in HA knock-down mice, suggesting induction of inflammation resulted in skin aging characterize by wrinkle formation. Oncogene expressions such as of tyrosine phosphatase, cyclin Y, and Rho were also down-regulated in HA-knock down mice. Our previous studies have demonstrated MU suppressed the metastasis of malignant tumor cells by inhibiting of HA production. Therefore, these results suggested that down-regulation of these oncogene expression, at least in part, were involved in inhibition of metastasis. On the other hand, gene expression of stromelysin 3, depredating enzyme of extracellular matrix components such as proteoglycan and collagen, strongly up-regulated. These data suggested that the degradation of extracellular matrix resulted in wrinkle formation of HA knock-down mice. Finally, we have administered HA and its oligosaccharides with various molecular weight. As the result, only intradermal injection of high molecular HA decreased skin aging, whereas no change was observed in aged skin by orally or topically administration. Also, skin aging was not reduced by introduction of aging-related gene which was down-regulated in HA knock-down mice, such as COL5A1, COL7A1, RHAMM, toll-like receptor 3, suggesting alone administration of each gene was not effective and cocktail therapy, the combination of multiple genes, was necessary of treatment of skin aging in HA knock-down mice Less

Report

(6 results)
  • 2011 Annual Research Report   Final Research Report ( PDF )
  • 2010 Annual Research Report   Self-evaluation Report ( PDF )
  • 2009 Annual Research Report
  • 2008 Annual Research Report
  • Research Products

    (34 results)

All 2012 2011 2010 2009 2008

All Journal Article (19 results) (of which Peer Reviewed: 4 results) Presentation (15 results)

  • [Journal Article] Potential of exogenous cartilage proteoglycan as a new material for cartilage regeneration2012

    • Author(s)
      Ohshika S, Ishibashi Y, Kon A, Kusumi T, Kijima H, Toh S
    • Journal Title

      Int Orthop

      Volume: 36 Issue: 4 Pages: 869-877

    • DOI

      10.1007/s00264-011-1335-2

    • Related Report
      2011 Annual Research Report 2011 Final Research Report
  • [Journal Article] Hyaluronan in the skin and its correlation with dermatopathology2011

    • Author(s)
      Kon A
    • Journal Title

      Trends in Glycosci Glycotechnol

      Volume: 22 Pages: 68-79

    • NAID

      10027508152

    • URL

      https://www.jstage.jst.go.jp/article/tigg/22/124/22_124_68/_pdf

    • Related Report
      2011 Final Research Report
  • [Journal Article] Expression of wild-type, but not mutant, loricrin causes programmed cell death in HaCaT keratinocytes2010

    • Author(s)
      Yoneda K, Demitsu T, Manabe M, Igarashi J, Kosaka H, Inagaki N, Takahashi H, Kon A, Kakurai M, Kubota Y
    • Journal Title

      J Dermatol

      Volume: 37 Issue: 11 Pages: 956-964

    • DOI

      10.1111/j.1346-8138.2010.00932.x

    • NAID

      10027572660

    • Related Report
      2011 Final Research Report
  • [Journal Article] Novel proteoglycan glycol-technology : chemoenzymatic synthesis of chondroitin sulfate-containing molecules and its application2010

    • Author(s)
      Yamaguchi M, Takagaki K, Kojima K, Hayashi N, Chen F, Kakizaki I, Kon A, Endo M
    • Journal Title

      Glycoconj J

      Volume: 27 Issue: 1 Pages: 189-198

    • DOI

      10.1007/s10719-009-9252-y

    • Related Report
      2011 Final Research Report
  • [Journal Article] Expression of wild-type, but not mutant, loricrin causes programmed cell death in HaCaT keratinocytes.2010

    • Author(s)
      Yoneda K, Demitsu T, Manabe M, Igarashi J, Kosaka H, Inagaki N, Takahashi H, Kon A, Kakurai M, Kubota Y
    • Journal Title

      J Dermatol 37

      Pages: 956-964

    • NAID

      10027572660

    • Related Report
      2010 Self-evaluation Report
  • [Journal Article] Novel proteoglycan glycotechnology : chemoenzymatic synthesis of chondroitin sulfate-containing molecules and its application.2010

    • Author(s)
      Yamaguchi M, Takagaki K, Kojima K, Hayashi N, Chen F, Kakizaki I, Kon A, Endo M
    • Journal Title

      Glycoconj J 27

      Pages: 189-198

    • Related Report
      2010 Self-evaluation Report
  • [Journal Article] Hyaluronan in the skin and its correlation with dermatopathology.2010

    • Author(s)
      Kon A
    • Journal Title

      Trends in Glycosci Glycotechnol 22

      Pages: 68-79

    • NAID

      10027508152

    • Related Report
      2010 Self-evaluation Report
  • [Journal Article] Hyaluronan in the skin and its correlation with dermatopathology.2010

    • Author(s)
      Kon A
    • Journal Title

      Trends in Glycoscience and Glycotechnology

      Volume: 22 Pages: 68-79

    • NAID

      10027508152

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Expression of wild-type, but not mutant, loricrin causes programmed cell death in HaCaT keratinocytes.2010

    • Author(s)
      Yoneda K, Demitsu T, Manabe M, Igarashi J, Kosaka H, Inagaki N, Takahashi H, Kon A, Kakurai M, Kubota Y
    • Journal Title

      J Dermatol

      Volume: 37 Pages: 956-964

    • NAID

      10027572660

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel proteoglycan glycotechnology : chemoenzymatic synthesis of chondroi-tin sulfate-containing molecules and its application.2010

    • Author(s)
      Yamaguchi M, Takagaki K, Kojima K, Hayashi N, Chen F, Kakizaki I, Kon A, Endo M
    • Journal Title

      Glycoconj J

      Volume: 27 Pages: 189-198

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hyaluronan in skin : its correlation with dermato-pathology2010

    • Author(s)
      Kon Atsushi
    • Journal Title

      Trends in Glycoscience and Glycotechnology (印刷中)

    • NAID

      10027508152

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 胎仔創傷治癒機構(scarless wound healing)2009

    • Author(s)
      今淳
    • Journal Title

      日皮会誌

      Volume: 119 Pages: 1971-1977

    • NAID

      10028277228

    • URL

      http://www.dermatol.or.jp/Journal/JpnJD/full/119101971j.pdf

    • Related Report
      2011 Final Research Report
  • [Journal Article] 胎仔創傷治癒機構(scarless wound healing)2009

    • Author(s)
      今淳
    • Journal Title

      日皮会誌 119

      Pages: 1971-1977

    • NAID

      10028277228

    • Related Report
      2010 Self-evaluation Report
  • [Journal Article] Hyaluronan knockdown mice : application to analysis of hyaluronan-mediated patho-physiology2008

    • Author(s)
      Kon A
    • Journal Title

      inflammation and Regeneration

      Volume: 28 Pages: 41-46

    • NAID

      10022602174

    • URL

      http://www.jsir.gr.jp/past_journal/2801/0041-0046.pdf

    • Related Report
      2011 Final Research Report
  • [Journal Article] Recent advances in skin aging research2008

    • Author(s)
      Kon A
    • Journal Title

      Fragrance J

      Volume: 36 Pages: 18-25

    • NAID

      40015866396

    • Related Report
      2011 Final Research Report
  • [Journal Article] Up-regulation of hyaluronan synthase genes in cultured human epidermal keratinocytes by UVB irradiation2008

    • Author(s)
      Kakizaki I, Itano N, Kimata K, Hanada K, Kon A, Yamaguchi M, Takahashi T, Takagaki K
    • Journal Title

      Arch Biochem Biophys

      Volume: 471 Pages: 85-93

    • URL

      http://dx.doi.org/10.1016/j.abb.2007.12.004

    • Related Report
      2011 Final Research Report
  • [Journal Article] Up-regulation of hyaluronan synthase genes in cultured human epidermal keratinocytes by UVB irradiation2008

    • Author(s)
      Kakizaki I, Itano N, Kimata K, Hanada K, Kon A, Yamaguchi M, Takahashi T, Takagaki K
    • Journal Title

      Arch Biochem Biophys 471

      Pages: 85-93

    • Related Report
      2010 Self-evaluation Report
  • [Journal Article] ヒアルロン酸ノックダウンマウスの開発及び病態解析への適用炎症再生2008

    • Author(s)
      今淳
    • Journal Title

      28

      Pages: 41-46

    • Related Report
      2010 Self-evaluation Report
  • [Journal Article] 最近の抗老化/抗酸化研究と抗老化剤の開発-皮膚の老化研究の最新動向2008

    • Author(s)
      今淳
    • Journal Title

      Fragrance J 36

      Pages: 18-25

    • Related Report
      2010 Self-evaluation Report
  • [Presentation] 4-メチルウンベリフェロンによるヒアルロン酸関連遺伝子の発現調節について2012

    • Author(s)
      今淳, 板先解子
    • Organizer
      2011年度青森県保健医療福祉研究発表会
    • Place of Presentation
      青森市
    • Related Report
      2011 Annual Research Report 2011 Final Research Report
  • [Presentation] 皮膚から全身に向けてのアンチエイジング2010

    • Author(s)
      今淳
    • Organizer
      青森県栄養士会平成22年度生涯学習カリキュラム
    • Place of Presentation
      青森市
    • Related Report
      2011 Final Research Report
  • [Presentation] 4-メチルウンベリフェロンによる皮膚のヒアルロン酸合成の抑制機構について2010

    • Author(s)
      乗鞍敏夫, 数馬恒平, 渡部朋子, 渡部一郎, 山口真範, 今淳
    • Organizer
      第42回日本結合組織学会学術大会,第57回マトリックス研究会大会合同集会
    • Place of Presentation
      秋田
    • Related Report
      2011 Final Research Report 2010 Self-evaluation Report
  • [Presentation] 4-メチルウンベリフェロンによる皮膚のヒアルロン酸合成の抑制機構について2010

    • Author(s)
      乗鞍敏夫, 数馬恒平, 渡部朋子, 渡部一郎, 山口真範,今淳
    • Organizer
      第42回日本結合組織学会学術大会,第57回マトリックス研究会大会合同集会
    • Place of Presentation
      秋田市
    • Related Report
      2010 Annual Research Report
  • [Presentation] Skin aging and extracellular matrix2009

    • Author(s)
      Kon A
    • Organizer
      Korean photobiology meeting
    • Place of Presentation
      Seoul
    • Year and Date
      2009-06-20
    • Related Report
      2011 Final Research Report
  • [Presentation] Skin aging and extracellular matrix.2009

    • Author(s)
      Kon A
    • Organizer
      Korean photobiology meeting
    • Place of Presentation
      Seoul(招待講演)
    • Year and Date
      2009-06-20
    • Related Report
      2010 Self-evaluation Report
  • [Presentation] 4-methyl-umbelliferone-mediated inhibition of hyaluronan expression in epidermal keratinocytes and dermal fibroblasts2009

    • Author(s)
      Kon A, Watanabe T, Norikura T, Watanabe I, Kazuma C
    • Organizer
      第34回日本研究皮膚科学会年次学術大会
    • Place of Presentation
      福岡
    • Related Report
      2011 Final Research Report 2010 Self-evaluation Report
  • [Presentation] 4-メチルウンベリフェロンによる皮膚のヒアルロン酸合成抑制機構について2009

    • Author(s)
      今淳, 渡部朋子, 乗鞍敏夫, 渡部一郎, 数馬浩平
    • Organizer
      第82回日本生化学会大会
    • Place of Presentation
      神戸
    • Related Report
      2011 Final Research Report 2010 Self-evaluation Report 2009 Annual Research Report
  • [Presentation] 閉経後女性のヘルスケアのための新展開-皮膚の老化2009

    • Author(s)
      今淳
    • Organizer
      第24回日本更年期医学会学術集会
    • Place of Presentation
      青森
    • Related Report
      2011 Final Research Report
  • [Presentation] 4-メチルウンベリフェロンによるヒアルロン酸の合成抑制機構2009

    • Author(s)
      今淳, 数馬恒平, 渡部朋子, 渡部一郎, 五十嵐愛美, 高垣啓一
    • Organizer
      第9回日本抗加齢医学会総会
    • Place of Presentation
      横浜
    • Related Report
      2011 Final Research Report 2010 Self-evaluation Report
  • [Presentation] 新規なプロテオグリカン糖鎖工学:コンドロイチン硫酸含有分子の化学-酵素的合成とその応用2009

    • Author(s)
      山口真範, 高垣啓一, 柿崎育子, 今淳, 遠藤正彦
    • Organizer
      第82回日本生化学会大会
    • Place of Presentation
      神戸
    • Related Report
      2010 Self-evaluation Report
  • [Presentation] 閉経後女性のヘルスケアのための新展開皮膚の老化2009

    • Author(s)
      今淳
    • Organizer
      第24回日本更年期医学会学術集会
    • Place of Presentation
      ワークショップ
    • Related Report
      2010 Self-evaluation Report
  • [Presentation] メチルウンベリフェロン誘導体 : 悪性腫瘍のヒアルロン酸合成及び転移に対する抑制効果の比較2008

    • Author(s)
      今 淳, 五十嵐愛美, 諸橋一
    • Organizer
      第29回日本炎症・再生医学会
    • Place of Presentation
      東京
    • Year and Date
      2008-07-08
    • Related Report
      2008 Annual Research Report
  • [Presentation] 4-メチルウンベリフェロン誘導体:悪性腫瘍のヒアルロン酸合成及び転移に対する抑制効果の比較検討2008

    • Author(s)
      今淳, 五十嵐愛美, 諸橋一
    • Organizer
      第29回日本炎症・再生医学会
    • Place of Presentation
      東京
    • Related Report
      2010 Self-evaluation Report
  • [Presentation] 組織工学的手法を用いた関節軟骨修復への糖鎖の応用2008

    • Author(s)
      大鹿周佐, 上里涼子, 石橋恭之, 今淳, 楠美智巳, 鬼島宏, 高垣啓一, 藤哲
    • Organizer
      第2回東北糖鎖研究会
    • Place of Presentation
      弘前
    • Related Report
      2010 Self-evaluation Report

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Published: 2008-04-01   Modified: 2016-04-21  

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