自己終息シグナル解明に基づく抗血管、リンパ管新生治療への応用

• Project/Area Number: 18013019
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: 南 敬 The University of Tokyo, 先端科学技術研究センター, 科学技術振興特任教員(特任准教授) (00345141)
• Co-Investigator(Kenkyū-buntansha): 河合 佳子 信州大学, 医学部, 助教 (10362112)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥10,300,000 (Direct Cost: ¥10,300,000); Fiscal Year 2007: ¥4,900,000 (Direct Cost: ¥4,900,000); Fiscal Year 2006: ¥5,400,000 (Direct Cost: ¥5,400,000)
• Keywords: NFATc / DSCR-1s / Hprt-locus / Egr3 / GATA / Heterogeneity / Endothelial cells / Feedback / VEGF / 血管内皮細胞 / LPS / MFTc / ダウン症候群関連因子-1 / Egr-3 / Hprt-target mouse / heterogeneity

Research Abstract

血管新生促進因子であるVEGF/Thrombin刺激によってCn-NFATc経路が活性化され、その特異的feedback因子であるダウン症候群関連因子short-isoform(DSCR-1s)が誘導されること、本因子のpromoter領域をマウスの特定領域(Hprt-locus)にknock-inしたマウスの樹立に成功したことを昨年度までに報告した。そこで、本マウスを用い包括的なDSCR-1s発現のin vivo機構解析存行ったところ、DSCR-1sはマウスembryo(E10-14)では広範囲にわたる強い血管内皮特異的な発現様式を示すが、その後大きく発現は減少し、adultマウスでは局所的に弱い発現を示すことが明らかとなった。しかし、マウスにLPSやVEGFの刺激を付加することによって臓器特異的(脳、心臓、腎臓、肺)かつ血管選択的にDSCR-1sが誘導される興味深い結果が得られた。また腫瘍xenograft環境下では強い血管、リンパ管内皮特異的な発現様式を示した。
DSCR-1s promoter上にはNFArcとGATAの結合部位があるが、NFATc1,c2,c3及びGATA2が制御に深く関わっていること、さらにDSCR-1sの内皮特異的な安定発現により、血管新生、肺への腫瘍細胞の転移が顕著に抑制されることを見いだした(投稿中)。また血管内皮での遺伝子発現において重要とされるGATA転写因子であるが、微小血管内皮と大血管で発現するGATA因子の組み合わせが異なり、特にTie2の発現に関しては微小血管、リンパ管内皮ではGATA2が、大血管内皮ではGATA3が主要な役割を担っていることを明らかにした(投稿中)。続いて内皮活性化刺激でDSCR-1sに次いで誘導されるEgr-3についてもその生理的意義を解析し、これがVEGF依存性の増殖、管腔形成に深く寄与することを見いだしている。

Research Products

• [Journal Article] Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1. (2008)
  • Author(s): Fukuhara, S., Sako, K., Minami, T., Noda, K., Kim, HZ., Kodama, T., Shibuya, M., Takakura, N., Koh, GY. And Mochizuki, N.
  • Journal Title: Nature Cell Biol. 10 Pages: 513-26
  • Peer Reviewed
• [Journal Article] Heterogeneity in immunohistochemical, genomic, and biological properties of human lymphatic endothelial cells between initial and collecting lymph vessels. (2008)
  • Author(s): Kawai, Y., Hosaka, K., Kaidoh, M., Minami, T., Kodama, T., and Ohhashi, T.
  • Journal Title: Lymphat. Res. Biol. 6 Pages: 15-27
  • Peer Reviewed
• [Journal Article] Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling (2007)
  • Author(s): Nakaoka, Y., Nishida, K., Narimatsu, M., Kamiya, A., Minami, T., Sawa, H., Okawa, K., Fuji, Y., Koyama, T., Maeda, M., Sane, M., Yamasaki, S., Arai, Y., Koh, G.Y., Kodama, T., Hirota, H., Otsu, K., Hirano, T., and Mochizuki, N.
  • Journal Title: J. Clin. Invest. 117 Pages: 1771-81
  • Peer Reviewed
• [Journal Article] Characterization and microarray analysis of genes in human lymphatic endothelial cells from patients with breast cancer. (2007)
  • Author(s): Kawai, Y., Minami, T., Fujimori, M., Hosaka, K., Mizuno, R., Ikomi, F., Kodama, T. and Ohhashi, T.
  • Journal Title: Lymph. Res. Biol. 5 Pages: 115-26
  • Peer Reviewed
• [Journal Article] A three-kilobase fragment of the human Robo4 promoter directs cell type-specific expression in endothelium. (2007)
  • Author(s): Okada, Y., Yano, K., Jin, E., Funahashi, N., Kitayama, M., Doi, T., Spokes, K., Beeler, D.L., Shih, S.C., Okada, H., Danilov, T.A., Maynard, E., Minami, T., Oettgen, P., and Aird, W.C.
  • Journal Title: Circ Res. 100 Pages: 1712-22
  • Peer Reviewed
• [Journal Article] Shear stress stabilizes NF-E2-related factor 2 and induces antioxidant genes in endothelial cells : role of reactive oxygen/nitrogen species. (2007)
  • Author(s): Warabi, N., Takabe, W., Minami, T., Inoue, K., Itoh, K., Yamamoto, M., Ishii, T., Kodama, T., and Noguchi, N.
  • Journal Title: Free Radic Biol Med. 42 Pages: 260-9
  • Peer Reviewed
• [Journal Article] Characterization and microarray analysis of genes in human lymphatic endothelial cells from patients with breast cancer (2007)
  • Author(s): Kawai, Y., Minami, T., Fujimori, M., Hosaka, K., Mizuno, R., Ikomi, F., Kodama, T., Ohhashi, T
  • Journal Title: Lympatic Research and Biology (In press)(印刷中)
• [Journal Article] Histone Deacetylase Inhibitor Reduces Monocyte Adhesion to Endothelium Through the Suppression of Vascular Cell Adhesion Molecule-1 Expression. (2006)
  • Author(s): Inoue, K., Kobayashi, M., Yano, K., Miura, M., Izumi, A., Mataki, C., Doi, T., Hamakubo, T., Reid, P.C., Hume, D.A., Yoshida, M., Aird, W.C., Kodama, T., Minami, T.
  • Journal Title: Arterioscler Thromb Vasc Biol. 26(12) Pages: 2652-2659
• [Journal Article] Wilms' tumor 1-associating protein regulates G2/M transition through stabilization of cyclin A2 mRNA. (2006)
  • Author(s): Minami, T., Horiuchi, K., Umetani, M., Okayama, H., Takada, S., Yamamoto, M., Aburatani, H., Reid, P.C., Housman, D.E., Hamakubo, T., Kodama, T.contributed eaually
  • Journal Title: Proc Natl. Am. Sci. 103(46) Pages: 17278-17283
• [Journal Article] A novel class of VEGF-responsive genes that require forkhead activity for expression. (2006)
  • Author(s): Abid, M.R., Shih, S.C., Out, H.H., Spokes, K.C., Okada, Y., Curiel, D.T., Minami, T., Aird, W.C.
  • Journal Title: J Biol Chem. 281(46) Pages: 35544-35553
• [Journal Article] Thrombin-induced auto-inhibitory factor, down syndrome critical region-1, attenuates NFAT-dependent vascular cell adhesion molecule-1 expression and inflammation in endothelium. (2006)
  • Author(s): Minami, T., Miura, M., Aird, W.C., Kodama, T.
  • Journal Title: J Biol Chem 281(29) Pages: 20503-20520
• [Presentation] NFATc-and SRF-induced Egrly Growth Response (Egr)-3 is Essential for VEGF-mediated Endothelial Cell Migration and Tube formation (2007)
  • Author(s): Suehiro, J and Minami, T
  • Organizer: American Heart Association, Scientific Sessions 2007
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2007-11-06
• [Presentation] GATA3 Expression is Essential for Tie2 Expression and Angiopoietin-1/Tie2-mediated Signaling in Endothelium (2007)
  • Author(s): Song, H and Minami, T.
  • Organizer: American Heart Association, Scientific Sessions 2007
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2007-11-05
• [Presentation] Inflammation-mediated Down Syndrome Critical Region (DSCR)-2 Promoter Activation Shows Vascular-bed Specific Patterns in Hprt-locus targeted transgenic mice (2007)
  • Author(s): Minami, T
  • Organizer: Americall Heart Association, Scientific Sessions 2007
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 2007-11-04
• [Book] Endothelial Biomedicine (2007)
  • Author(s): Minaml, T., William C. Aird
  • Total Pages: 12
  • Publisher: Cambridge Press
• [Remarks]
  • URL: http://www.1sbm.org