神経・動脈・静脈は、なぜ併走するのか？－皮膚発生モデルを用いた解析－

• Project Area: Vasculo-neural wiring and their interdependent crosstalk
• Project/Area Number: 23122511
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Osaka University
• Principal Investigator: 木戸屋 浩康 大阪大学, 微生物病研究所, 助教 (00543886)
• Project Period (FY): 2011-04-01 – 2013-03-31
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2012: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2011: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
• Keywords: 血管形成 / 発生 / 再生 / 血管新生 / 血管と神経 / ワイヤリング

Outline of Annual Research Achievements

本申請研究では、マウス皮膚の発生モデルを利用する解析系により、神経-動脈-静脈の走行性制御のメカニズムおよび走行性がもたらす生理的意義の解明を目的として研究を行う。神経-動脈-静脈が併走する分岐パターンを示すことは古くから認知されているが、血管と神経がどのような相互作用を持つか、走行性が実際にどのような生理現象に重要であるかなどは明確になっていない。
我々は血管形成過程において特異的に発現が上昇する生理活性オリゴペプチドapelinおよびその受容体APJに注目して解析を進めた。まず、Apelin / APJ 系が動脈-静脈のパターニングにおいてどのような役割を果たすかを調べるために、Apelin およびAPJ 欠損マウスの胎児期の皮膚を解析した。また、Apelin / APJ 系の下流シグナルがどのような分子群の発現を誘導するかを、マイクロアレイによる網羅的解析により明らかにした。
加えて、血管神経の走行性の生理的意義を検討するため、走行性に以上が認められるモデルマウスを作成し解析を行った。その結果、神経-動脈-静脈の走行性が様々な成体の恒常性維持に関与していることが明らかになった。

Research Progress Status

24年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

24年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Critical role of Trib1 for the differentiation of adipose tissue-resident macrophages maintaining metabolic homeostasis. (2013)
  • Author(s): Satoh T, Kidoya H, Naito H, Yamamoto M, Takemura N, Nakagawa K, Yoshioka Y, Morii E, Takakura N, Takeuchi O, Akira S
  • Journal Title: Nature Volume: 495(7442) Issue: 7442 Pages: 524-528
  • DOI: 10.1038/nature11930
  • Peer Reviewed
• [Journal Article] An angiogenic role for adrenomedullin in choroidal neovascularization. (2013)
  • Author(s): Sakimoto S, Kidoya H, Kamei M, Naito H, Yamakawa D, Sakaguchi H, Wakabayashi T, Nishida K, Takakura N.
  • Journal Title: PLoS One Volume: 8 Issue: 3 Pages: e58096-e58096
  • DOI: 10.1371/journal.pone.0058096
  • Peer Reviewed
• [Journal Article] The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy. (2012)
  • Author(s): Kidoya H, Kunii N, Naito H, Muramatsu F, Okamoto Y, Nakayama T, Takakura N.
  • Journal Title: Oncogene Volume: 31(27) Pages: 3254-3264
  • Peer Reviewed
• [Journal Article] Promotion of Lymphatic Integrity by Angiopoietin-1/Tie2 Signaling during Inflammation (2012)
  • Author(s): Kajiya K.
  • Journal Title: Am J Pathol. Volume: 180 Issue: 3 Pages: 1273-1282
  • DOI: 10.1016/j.ajpath.2011.11.008
  • Peer Reviewed
• [Journal Article] A role for endothelial cells in promoting the maturation of astrocytes through the apelin/APJ system in mice (2012)
  • Author(s): Sakimoto S.
  • Journal Title: Development Volume: (In press) Issue: 7 Pages: 1327-1335
  • DOI: 10.1242/dev.072330
  • Peer Reviewed
• [Journal Article] microRNA-125b inhibits tube formation of blood vessels through translational suppression of VE-cadherin (2012)
  • Author(s): Muramatsu F.
  • Journal Title: Oncogene Volume: (In press) Issue: 4 Pages: 414-421
  • DOI: 10.1038/onc.2012.68
  • Peer Reviewed
• [Journal Article] Biology of the apelin-APJ axis in vascular formation. (2012)
  • Author(s): Kidoya H, Takakura N.
  • Journal Title: J Biochem Volume: 152(2) Issue: 2 Pages: 125-131
  • DOI: 10.1093/jb/mvs071
  • NAID: 10031166121
  • Peer Reviewed
• [Journal Article] The transcription factor Jun dimerization protein 2 controls bone homeostasis and antibacterial immunity by regulating osteoclast and neutrophil differentiation (2012)
  • Author(s): kenta Maruyama, Masahiro Fukasaka, Alexis Vandenbon, Tatsuya Saitoh, Takumi Kawasaki, Takeshi Kondo, Kazunari K. Yokoyama, Hiroyasu Kidoya, Nobuyuki Takakura, Daron Standley, Osamu Takeuchi, and Shizuo Akira
  • Journal Title: Immunity Volume: 37 Issue: 6 Pages: 1024-1036
  • DOI: 10.1016/j.immuni.2012.08.022
  • Peer Reviewed
• [Journal Article] The apelin/APJ system induces maturation of the tumor vasculature and improves the efficiency of immune therapy (2012)
  • Author(s): Kidoya H.
  • Journal Title: Oncogene Volume: (In press) Issue: 27 Pages: 3254-64
  • DOI: 10.1038/onc.2011.489
  • Peer Reviewed
• [Journal Article] Apelin attenuates UVB-induced edema and inflammation by promoting vessel function (2011)
  • Author(s): Sawane M.
  • Journal Title: Am J Pathol. Volume: 179 Issue: 6 Pages: 2691-2697
  • DOI: 10.1016/j.ajpath.2011.08.024
  • Peer Reviewed
• [Journal Article] 2-Methoxycinnamaldehyde inhibits tumor angiogenesis by suppressing Tie2 activation (2011)
  • Author(s): Yamakawa D, Kidoya H, Sakimoto S, Jia W, Takakura N
  • Journal Title: Biochem Biophys Res Commun Volume: 415(1) Pages: 174-180
  • Peer Reviewed
• [Journal Article] Changes in blood vessel maturation in the fibrous cap of the tumor rim (2011)
  • Author(s): Naito H.
  • Journal Title: Cancer Sci. Volume: 103 Issue: 3 Pages: 433-438
  • DOI: 10.1111/j.1349-7006.2011.02157.x
  • Peer Reviewed
• [Journal Article] Identification and characterization of a resident vascular stem/ progenitor cell population in preexisting blood vessels (2011)
  • Author(s): Naito H, Kidoya H, Sakimoto S, Wakabayashi T, Takakura N
  • Journal Title: EMBO J. Volume: 31 Issue: 4 Pages: 842-855
  • DOI: 10.1038/emboj.2011.465
  • Peer Reviewed
• [Presentation] Regulation of vascular maturation by apelin-APJ and its application for angiogenic therapy. (2012)
  • Author(s): Hiroyasu Kidoya, Nobuyuki TakakuraHiroyasu Kidoya, Hisamichi Naito, Naoki Kunii, Nobuyuki Takakura.
  • Organizer: 第20回日本血管生物医学会学術集会 The 10th Korea-Japan Joint Symposium on Vascular Biology
  • Place of Presentation: 徳島
  • Year and Date: 2012-12-05
  • Invited
• [Presentation] Role of secreted frizzled-related protein-1 in tumor angiogenesis. (2012)
  • Author(s): Hiroyasu Kidoya, Nobuyuki Takakura.
  • Organizer: 第71回 日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-20
• [Presentation] Maturation Of The Tumor Blood Vessels Induced By Apelin/APJ System Improves The Efficiency Of Immunotherapy. (2012)
  • Author(s): H. Kidoya, N. Kunii, H. Naito, F. Muramatsu, N. Takakura.
  • Organizer: Cell symposia: Angiogenesis, Metabolic Regulation, and Cancer Biology in association with VIB
  • Place of Presentation: Katholieke Universiteit, Leuven, Belgium.
  • Year and Date: 2012-07-06
• [Presentation] 血管成熟化因子「Apelin」を用いた、新概念の血管再生療法の開発 (2012)
  • Author(s): 木戸屋浩康、高倉伸幸
  • Organizer: 第49回日本臨床分子医学会学術集会
  • Place of Presentation: 京都
  • Year and Date: 2012-04-13
• [Presentation] microRNA-125b inhibits tumor vascular formation through translational suppression of VE-cadherin (2011)
  • Author(s): Hiroyasu Kidoya, Fumitaka Muramatsu, Hisamichi Naito, Susumu Sakimoto, Taku Wakabayashi, Chie Takeshita, Nobuyuki Takakura
  • Organizer: The 9th Japan-Korea Joint Symposium on Vascular Biology
  • Place of Presentation: Busan, Korea
• [Presentation] Maturation of the tumor blood vessels induced by apelin/APJ system improves the efficiency of immunotherapy. The Second Pacific Symposium on Vascular Biology (2011)
  • Author(s): Hiroyasu Kidoya, Naoki Kunii, Hisamichi Naito, Susumu Sakimoto, Taku Wakabayashi, Chie Takeshita, Fumitaka Muramatsu, Nobuyuki Takakura
  • Organizer: The 9th Japan-Korea Joint Symposium on Vascular Biology
  • Place of Presentation: Jeju Island, Korea
• [Book] 血管生物医学事典 (2011)
  • Author(s): 木戸屋浩康
  • Publisher: 朝倉書店(2011年12月10日)
• [Remarks] 微生物病研究所ホームページ
  • URL: http://st.biken.osaka-u.ac.jp/member/kidoya.html
• [Remarks] 大阪大学 研究者総覧
  • URL: http://www.dma.jim.osaka-u.ac.jp/view?l=jau=7708
• [Remarks]
  • URL: http://st.biken.osaka-u.ac.jp/member/kidoya.html
• [Remarks]
  • URL: http://www.dma.jim.osaka-u.ac.jp/kg-portal/aspi/RX0011D.asp?UNO=19906&seq=1206