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Biochemical process of membrane-associated protein is induced by inflammatory cytokines in cultured lymphatic endothelial cells

Research Project

Project/Area Number 23390283
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Dermatology
Research InstitutionHamamatsu University School of Medicine

Principal Investigator

HIRAKAWA Satoshi  浜松医科大学, 医学部, 准教授 (50419511)

Co-Investigator(Renkei-kenkyūsha) HIGASHIYAMA Shigeki  愛媛大学, プロテオ医学研究センター, 教授 (60202272)
Project Period (FY) 2011-04-01 – 2014-03-31
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥19,500,000 (Direct Cost: ¥15,000,000、Indirect Cost: ¥4,500,000)
Fiscal Year 2013: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2012: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2011: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
Keywords増殖因子 / リンパ管新生 / 細胞内シグナル伝達 / 遺伝子改変マウス / シグナル伝達 / 細胞間接着 / ヒアルロン酸 / 血管新生 / 細胞遊走 / 治療 / 血管内皮増殖因子 / シェディング / 細胞内シグナル
Research Abstract

The present study demonstrated that inflammatory cytokines induces the ectodomain shedding of type I transmembrane proteins in cultured human lymphatic endothelial cells. ADAM17 is responsible for the shedding via the activation of MAP kinase pathway in response to vascular endothelial factor (VEGF)-A. Furthermore, the entodomain shedding of membrane-associated protein enhanced the migration of cultured lymphatic endothelial cells in response to VEGF-A. Moreover, double immunofluorescence analysis revealed that the targeted overexpression of VEGF-A promoted the ectodomain shedding of the membrane associated protein cutaneous lymphatic vessels. Therefore, these results indicate, for the first time, that lymphangiogensis is mediated by the biochemical process of membrane-binding proteins in lymphatic endothelial cells in vitro and in vivo.

Report

(4 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Annual Research Report
  • 2011 Annual Research Report
  • Research Products

    (47 results)

All 2014 2013 2012 2011 2010 Other

All Journal Article (21 results) (of which Peer Reviewed: 9 results) Presentation (17 results) (of which Invited: 5 results) Book (4 results) Remarks (1 results) Patent(Industrial Property Rights) (4 results) (of which Overseas: 1 results)

  • [Journal Article] accelerates carcinogenesis by activating chronic inflammation and oxidative stress2014

    • Author(s)
      Aoi J, Endo M, Kadomatsu T, Miyata K, Ogata A, Horiguchi H, Odagiri H, Masuda T, Fukushima S, Jinnin M, Hirakawa S, Sawa T, Akaike T, Ihn H, Oike Y
    • Journal Title

      Mol Cancer Res

      Volume: 12 Pages: 239-49

    • Related Report
      2013 Final Research Report
  • [Journal Article] Lymphangiogenesis and angiogenesis in abdominal aortic aneurysm2014

    • Author(s)
      Sano M, Sasaki T, Hirakawa S, Sakabe J, Ogawa M, Baba S, Zaima N, T anaka H, Inuzuka K, Y amamoto N, Setou M, Sato K, Konno H, Unno N
    • Journal Title

      PLoS ONE

      Volume: 20;9(3)

    • Related Report
      2013 Final Research Report
  • [Journal Article] Lymphatics in nanophysiology2014

    • Author(s)
      Hirakawa S, Detmar M, Karaman S.
    • Journal Title

      Advanced Drug Delivery Reviews

      Volume: 印刷中 Pages: 12-18

    • DOI

      10.1016/j.addr.2014.01.011

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Serum interleukin-22 and vascular endothelial growth factor serve as sensitive biomarkers but not as predictors of therapeutic response to biologics in patients with psoriasis2013

    • Author(s)
      Shimauchi T, Hirakawa S, Suzuki T, Yasuma A, Majima Y, Tatsuno K, Yagi H, Ito T, Tokura Y
    • Journal Title

      J Dermatol

      Volume: 40 Pages: 805-12

    • Related Report
      2013 Final Research Report
  • [Journal Article] High frequencies of positive nickel/cobalt patch tests and high sweat nickel concentration in patients with intrinsic atopic dermatitis2013

    • Author(s)
      Yamaguchi H, Kabashima-Kubo R, Bito T, Sakabe J-I, Shimauchi T, Ito T, Hirakawa S, Hirasawa N, Ogasawara K, T okura Y
    • Journal Title

      J Dermatol Sci

      Volume: 72 Pages: 240-5

    • Related Report
      2013 Final Research Report
  • [Journal Article] Kallikrein-related Peptidase 5 Functions in Proteolytic Processing of Profilaggrin in Cultured Human Keratinocytes2013

    • Author(s)
      Sakabe J, Y amamoto M, Hirakawa S, Motoyama A, Ohta I, T atsuno K, Ito T, Kabashima K, Hibino T, T okura Y
    • Journal Title

      J Biol Chem

      Volume: 14;288 Pages: 17179-89

    • Related Report
      2013 Final Research Report
  • [Journal Article] Kallikrein-related Peptidase 5 Functions in Proteolytic Processing of Profilaggrin in Cultured Human Keratinocytes2013

    • Author(s)
      Sakabe J, Y amamoto M, Hirakawa S, Motoyama A, Ohta I, Tatsuno K, Ito T, Kabashima K, Hibino T, T okura Y
    • Journal Title

      J Biol Chem

      Volume: 14;288(24) Pages: 17179-89

    • Related Report
      2013 Final Research Report
  • [Journal Article] Topical simvastatin accelerates wound healing in diabetes by enhancing angiogenesis and lymphangiogenesis2012

    • Author(s)
      Asai J, Takenaka H, Hirakawa S, Sakabe J, Hagura A, Kishimoto S, Maruyama K, Kajiya K, Kinoshita S, T okura Y, Katoh N
    • Journal Title

      Am J Pathol

      Volume: 181(6) Pages: 2217-24

    • Related Report
      2013 Final Research Report
  • [Journal Article] Induced lymphatic sinus hyperplasia in sentinel lymph nodes by VEGF-C as the earliest premetastatic indicator2012

    • Author(s)
      Liersch R, Hirakawa S, Berdel WE, Mesters RM, Detmar M
    • Journal Title

      Int J Oncol

      Volume: 41(6) Pages: 2073-8

    • Related Report
      2013 Final Research Report
  • [Journal Article] A palmtop-sized microfluidic cell culture system driven by a miniaturized infusion pump2012

    • Author(s)
      Sasaki N, Shinjo M, Hirakawa S, Nishinaka M, Tanaka Y, Mawatari K, Kitamori T, Sato K
    • Journal Title

      Electrophoresis

      Volume: 33 Pages: 1729-1735

    • Related Report
      2013 Final Research Report
  • [Journal Article] Targeted overexpression of Angptl6/angiopoietin-related growth factor in the skin promotes angiogenesis and lymphatic vessel enlargement in response to ultraviolet B2012

    • Author(s)
      Okazaki H, Hirakawa S, Shudou M, Nakaoka Y, Shirakata Y, Miyata K, Oike Y, Hashimoto K, Sayama K
    • Journal Title

      J Dermatol

      Volume: 39 Pages: 366-74

    • NAID

      10031184909

    • Related Report
      2013 Final Research Report
  • [Journal Article] A palmtop-sized microfluidic cell culture system driven by a miniaturized infusion pump.2012

    • Author(s)
      Naoki Sasaki
    • Journal Title

      Electrophoresis

      Volume: 33 Issue: 12 Pages: 1729-1735

    • DOI

      10.1002/elps.201100691

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Targeted overexpression of Angpt16/angiopoietin-related growth factor in the skin promotes angiogenesis and lymphatic vessel enlargement in response to ultraviolet B2012

    • Author(s)
      Okazaki H, et al
    • Journal Title

      J Dermatol

      Volume: 39 Issue: 4 Pages: 366-74

    • DOI

      10.1111/j.1346-8138.2011.01396.x

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Topical simvastatin accelerates wound healing in diabetes by enhancing angiogenesis and lymphangiogenesis2012

    • Author(s)
      Jun Asai
    • Journal Title

      The American Journal of Pathology

      Volume: 181 Issue: 6 Pages: 2217-2224

    • DOI

      10.1016/j.ajpath.2012.08.023

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Twist1 as a possible biomarker for metastatic basal cell carcinoma.2012

    • Author(s)
      Yuta Majima
    • Journal Title

      Acta Dermato-Venereologica

      Volume: 92 Issue: 6 Pages: 621-622

    • DOI

      10.2340/00015555-1422

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Induced lymphatic sinus hyperplasia in sentinel lymph nodes by VEGF-C as the earliest premetastatic indicator.2012

    • Author(s)
      Rudiger Liersch
    • Journal Title

      International Journal of Oncology

      Volume: 41 Issue: 6 Pages: 2073-2078

    • DOI

      10.3892/ijo.2012.1665

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Haemodialysis-induced pseudoporphyria successfully treated with glutathione2012

    • Author(s)
      Kasuya A, Hashizume H, Hirakawa S, Tokura Y
    • Journal Title

      European Journal of Dermatology

      Volume: 22 Issue: 1 Pages: 137-138

    • DOI

      10.2340/00015555-1371

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Angiopoietin-like protein 2 is an important facilitator of inflammatory carcinogenesis and metastasis2011

    • Author(s)
      Aoi J, Endo M, Kadomatsu T, Miyata K, Nakano M, Horiguchi H, Ogata A, Odagiri H, Y ano M, Araki K, Jinnin M, Ito T, Hirakawa S, Ihn H, Oike Y
    • Journal Title

      Cancer Res

      Volume: 71 Pages: 7502-12

    • Related Report
      2013 Final Research Report
  • [Journal Article] Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse2011

    • Author(s)
      Kerjaschki D, Bago-Horvath Z, Rudas M, Sexl V, Schneckenleithner C, Wolbank S, Bartel G, Krieger S, Kalt R, Hantusch B, Keller T, Nagy-Bojarszky K, Huttary N, Raab I, Lackner K, Krautgasser K, Schachner H, Kaserer K, Rezar S, Madlener S, Vonach C, Davidovits A, Nosaka H, Hämmerle M, Viola K, Dolznig H, Schreiber M, Nader A, Mikulits W, Gnant M, Hirakawa S, Detmar M, Alitalo K, Nijman S, Offner F, Maier TJ, Steinhilber D, Krupitza G
    • Journal Title

      J Clin Invest

      Volume: 121 Pages: 2000-12

    • Related Report
      2013 Final Research Report
  • [Journal Article] Raynaud's phenomenon, digital gangrene and hypergammaglobulinemic purpura occurring in a patient with IgG4-related disease2011

    • Author(s)
      Ikawa T, Kasuya A, Hirakawa S, Tokura Y
    • Journal Title

      Br J Dermatol

      Volume: 165 Issue: 6 Pages: 1359-1366

    • DOI

      10.1111/j.1365-2133.2011.10609.x

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Multiple milia and comedones as a skin manifestation of systemic amyloidosis2011

    • Author(s)
      Funai N, Machida S, Ito T, Hirakawa S, Tokura Y
    • Journal Title

      European Journal of Dermatology

      Volume: 21 Pages: 638-639

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Presentation] Nanophysiology to better understand the function of the vasculature in health and skin disease2014

    • Author(s)
      Hirakawa S
    • Organizer
      The 24th Annual Meeting of The Korean Society for Investigative Dermatology
    • Place of Presentation
      Seoul, South Korea
    • Related Report
      2013 Final Research Report
  • [Presentation] Nanophysiology to better understand the function of the vasculature in health and skin disease.2014

    • Author(s)
      Hisakawa S.
    • Organizer
      The 24th annual meeting of the Korean Society for Investigative Dermatology
    • Place of Presentation
      Seoul
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] 血管・リンパ管に着目した再生医療と応用2014

    • Author(s)
      平川聡史
    • Organizer
      第112回日本皮膚科学会総会・学術大会
    • Place of Presentation
      横浜
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] 皮膚と循環 : 血管・リンパ管から考える病態生理2013

    • Author(s)
      平川聡史
    • Organizer
      第90回日本生理学会大会. シンポジウム
    • Place of Presentation
      東京
    • Related Report
      2013 Final Research Report
  • [Presentation] 皮膚と循環:血管・リンパ管から考える病態生理2013

    • Author(s)
      平川聡史
    • Organizer
      第90回日本生理学会大会
    • Place of Presentation
      東京
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] New approaches for patho-physiological function in cutaneous lymphatic vessels2012

    • Author(s)
      平川聡史
    • Organizer
      第36回日本リンパ学会総会 シンポジウム3
    • Place of Presentation
      東京
    • Year and Date
      2012-06-30
    • Related Report
      2013 Final Research Report
  • [Presentation] A functional role of L YVE-1 in VEGF-A-induced lymphangiogenesis and psoriasis2012

    • Author(s)
      Hirakawa S
    • Organizer
      The 61st annual Montania Symposium
    • Place of Presentation
      Gleneden Beach, Oregon
    • Related Report
      2013 Final Research Report
  • [Presentation] Biological importance of nodal lymphangiogenesis in tumor metastasis2012

    • Author(s)
      Hirakawa S
    • Organizer
      Workshop Classic and Modern in Angiogenesis and Lymphangiogenesis
    • Place of Presentation
      Timisoara, Romania
    • Related Report
      2013 Final Research Report
  • [Presentation] New approaches for patho-physiological function in cutaneous lymphatic vessels.2012

    • Author(s)
      平川聡史
    • Organizer
      第36回日本リンパ学会総会.
    • Place of Presentation
      東京
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] An approach to fabricate the polymer hollow microneedle that targets dermal lymphatic vessels in the skin.2012

    • Author(s)
      Satoshi Hirakawa
    • Organizer
      The 37th Annual Meeting of the Japanese Society for Investigative Dermatology.
    • Place of Presentation
      那覇
    • Related Report
      2012 Annual Research Report
  • [Presentation] A functional role of LYVE-1 in VEGF-A-induced lymphangiogenesis and psoriasis.2012

    • Author(s)
      Satoshi Hirakawa
    • Organizer
      The 61st annual Montania Symposium
    • Place of Presentation
      アメリカ合衆国
    • Related Report
      2012 Annual Research Report
  • [Presentation] リンパ管新生とリンパ節転移の基礎的解析2011

    • Author(s)
      平川聡史
    • Organizer
      第35回日本リンパ学会総会 シンポジウム3 : リンパ行性癌転移
    • Place of Presentation
      東京
    • Year and Date
      2011-06-04
    • Related Report
      2013 Final Research Report
  • [Presentation] Pathological angiogenesis and lymphangiogenesis2011

    • Author(s)
      Hirakawa S
    • Organizer
      World Congress of Dermatology 2011
    • Place of Presentation
      Seoul, South Korea
    • Year and Date
      2011-05-24
    • Related Report
      2013 Final Research Report
  • [Presentation] 癌とリンパ管新生2011

    • Author(s)
      平川聡史
    • Organizer
      第100回日本病理学会総会 シンポジウム2腫瘍と間質 分子細胞組織からのアプローチ シンポジウム
    • Place of Presentation
      横浜
    • Year and Date
      2011-04-28
    • Related Report
      2013 Final Research Report
    • Invited
  • [Presentation] Lymphatic vessels in inflammation and tumor metastasis2011

    • Author(s)
      Hirakawa S
    • Organizer
      EC8 Zurich 2011. 8 th International Symposium on the Biology of Endothelial cell
    • Place of Presentation
      Zurich, Switzerland
    • Related Report
      2013 Final Research Report
  • [Presentation] Lymphatic vessels in inflammation and tumor metastasis2011

    • Author(s)
      平川聡史
    • Organizer
      EC8 Zurich 2011. 8^<th> International Symposium on the Biology of Endothelial cell
    • Place of Presentation
      チューリッヒ(スイス連邦共和国)
    • Related Report
      2011 Annual Research Report
  • [Presentation] VEGF-A induces the ectodomain shedding of L YVE-1 via MAPK pathway in cultured lymphatic endothelial cells2010

    • Author(s)
      平川聡史
    • Organizer
      第69回日本癌学会学術総会
    • Place of Presentation
      大阪
    • Related Report
      2013 Final Research Report
  • [Book] 母斑, 血管腫・脈管形成異常, 山口徹, 今日の治療指針2013

    • Author(s)
      平川聡史
    • Total Pages
      1127
    • Publisher
      医学書院, 東京都
    • Related Report
      2013 Final Research Report
  • [Book] 紫斑, 瀧川雅浩2013

    • Author(s)
      平川聡史
    • Publisher
      南江堂, 東京都
    • Related Report
      2013 Final Research Report
  • [Book] 血管新生研究の最先端2012

    • Author(s)
      平川聡史
    • Total Pages
      6
    • Publisher
      医薬ジャーナル社
    • Related Report
      2012 Annual Research Report
  • [Book] がん幹細胞2011

    • Author(s)
      平川聡史
    • Total Pages
      7
    • Publisher
      羊土社
    • Related Report
      2011 Annual Research Report
  • [Remarks]

    • URL

      http://www2.hama-med.ac.jp/w1b/derm/index.html

    • Related Report
      2013 Final Research Report
  • [Patent(Industrial Property Rights)] 分子標的薬の皮膚系細胞に対する傷害性を定量評価する方法2013

    • Inventor(s)
      山内豊彦, 青島正浩, 平川聡史
    • Industrial Property Rights Holder
      浜松ホトニクス株式会社, 浜松医科大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2013-08-30
    • Related Report
      2013 Final Research Report
  • [Patent(Industrial Property Rights)] 血管透過性亢進抑制作用の評価方法2013

    • Inventor(s)
      山内豊彦, 平川聡史, 山下 豊, 戸倉新樹
    • Industrial Property Rights Holder
      浜松ホトニクス株式会社, 浜松医科大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2013-02-25
    • Related Report
      2013 Final Research Report
  • [Patent(Industrial Property Rights)] 特許2013

    • Inventor(s)
      山内豊彦
    • Industrial Property Rights Holder
      山内豊彦
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2013-034570
    • Filing Date
      2013-02-25
    • Related Report
      2012 Annual Research Report
  • [Patent(Industrial Property Rights)] マイクロニードルアレイ装置2011

    • Inventor(s)
      平川聡史
    • Industrial Property Rights Holder
      田丸卓也
    • Filing Date
      2011-11-01
    • Related Report
      2011 Annual Research Report
    • Overseas

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Published: 2011-04-06   Modified: 2019-07-29  

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