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Regulation of vascular homeostasis by AM-RAMP2 system and its therapeutic application for vascular abnormalities.

Research Project

Project/Area Number 17K08588
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field General pharmacology
Research InstitutionShinshu University

Principal Investigator

Shindo Yuka  信州大学, 医学部, 研究員 (50507506)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords血管 / 血管新生 / 転移 / 心血管、血液
Outline of Final Research Achievements

We have reported that vasoactive peptide adrenomedullin (AM) and its receptor activity-modifying protein RAMP2 possess angiogenic function and regulate vascular homeostasis. On the other hand, AM and RAMP2 are highly expressed in various cancers. In this study, using drug-inducible endothelial cell-specific RAMP2 knockout mice (DI-E-RAMP2-/-), we analyzed the significance of AM-RAMP2 system in cancer angiogenesis and metastasis. In tumor implantation model, we found that angiogenesis of primary lesion was suppressed, whereas spontaneous lung metastasis was increased.
Vascular integrity regulated by the AM-RAMP2 system could thus be a hopeful therapeutic target for suppressing tumor metastasis.

Academic Significance and Societal Importance of the Research Achievements

病的血管新生は、癌をはじめ、様々な疾患の発症や病態と深く関わっている。今回我々は、アドレノメデュリン(AM)-RAMP2 システムが、血管の恒常性維持に関わっている一方で、その破綻によって血管の恒常性が障害され、癌細胞が転移しやすい環境=転移前土壌が形成されることを見出した。AM-RAMP2系による血管恒常性維持作用に介入し、これを制御することは、従来の治療法とは異なり、癌腫を問わない治療法の開発につながる可能性がある。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (25 results)

All 2020 2019 2018 2017 Other

All Journal Article (9 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 8 results,  Open Access: 1 results) Presentation (14 results) (of which Int'l Joint Research: 1 results) Remarks (2 results)

  • [Journal Article] Deficiency of the adrenomedullin-RAMP3 system suppresses metastasis through the modification of cancer-associated fibroblasts2020

    • Author(s)
      Dai K, Tanaka M, Kamiyoshi A, Sakurai T, Ichikawa-Shindo Y, Kawate H, Cui N, Wei Y, Tanaka M, Kakihara S, Matsui S, Shindo T
    • Journal Title

      Oncogene

      Volume: 39(9) Issue: 9 Pages: 1914-1930

    • DOI

      10.1038/s41388-019-1112-z

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Endogenous Calcitonin Gene-Related Peptide Deficiency Exacerbates Postoperative Lymphedema by Suppressing Lymphatic Capillary Formation and M2 Macrophage Accumulation2019

    • Author(s)
      Matsui S, Tanaka M, Kamiyoshi A, Sakurai T, Ichikawa-Shindo Y, Kawate H, Dai K, Cui N, Wei Y, Tanaka M, Kakihara S, Nakamura K, Yamauchi A, Ishida K, Tanaka S, Kawamata M, Shindo T
    • Journal Title

      Am J Pathol

      Volume: 189(12) Issue: 12 Pages: 2487-2502

    • DOI

      10.1016/j.ajpath.2019.08.011

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Regulation of cardiovascular development and homeostasis by the adrenomedullin-RAMP system2019

    • Author(s)
      Shindo T, Tanaka M, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Yamauchi A, Sakurai T.
    • Journal Title

      Peptides.

      Volume: 111 Pages: 55-61

    • DOI

      10.1016/j.peptides.2018.04.004

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Development of a novel model of central retinal vascular occlusion and the therapeutic potential of the adrenomedullin-RAMP2 system.2019

    • Author(s)
      Hirabayashi K, Tanaka M, Imai A, Toriyama Y, Iesato Y, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Dai K, Cui N, Wei Y, Nakamura K, Iida S, Matsui S, Yamauchi A, Murata T, Shindo T.
    • Journal Title

      Am J Pathol.

      Volume: 189 Pages: 449-466

    • DOI

      10.1016/j.peptides.2018.10.006

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Endogenous calcitonin gene-related peptide suppresses ischemic brain injuries and progression of cognitive decline2018

    • Author(s)
      Zhai L, Tanaka M, et al.
    • Journal Title

      J Hypertens.

      Volume: 36 Issue: 4 Pages: 876-891

    • DOI

      10.1097/hjh.0000000000001649

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Endogenous calcitonin gene-related peptide regulates lipid metabolism and energy homeostasis in male mice2017

    • Author(s)
      Liu T, Tanaka M, et al.
    • Journal Title

      Endocrinology

      Volume: 158 Issue: 5 Pages: 1194-1206

    • DOI

      10.1210/en.2016-1510

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Vasoprotective activities of the adrenomedullin-RAMP2 system in endothelial cells2017

    • Author(s)
      Xian X, Tanaka M, et al.
    • Journal Title

      Endocrinology

      Volume: 158 Issue: 5 Pages: 1359-1372

    • DOI

      10.1210/en.2016-1531

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Adrenomedullin Suppresses Vascular Endothelial Growth Factor-Induced Vascular Hyperpermeability and Inflammation in Retinopathy.2017

    • Author(s)
      Imai A, Toriyama Y, Iesato Y, Hirabayasi K, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Liu T, Xian X, Zhai L, Dai K, Tanimura K, Liu T, Cui N, Yamauchi A, Murata T, Shindo T
    • Journal Title

      American journal of Pathology

      Volume: 187(5) Issue: 5 Pages: 999-1015

    • DOI

      10.1016/j.ajpath.2017.01.014

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] アドレノメデュリン-RAMP2系は転移前土壌形成を抑制し、癌転移を抑制する2017

    • Author(s)
      田中愛、小山晃英、桜井敬之、神吉昭子、新藤優佳、河手久香、新藤隆行 他
    • Journal Title

      血管

      Volume: 40 Pages: 101-106

    • Related Report
      2017 Research-status Report
  • [Presentation] アドレノメデュリン-RAMP2系はヒト網膜色素上皮細胞の上皮間葉転換を抑制する2019

    • Author(s)
      田中正明、平林一貴、今井章、鳥山佑一、家里康弘、桜井敬之、神吉昭子、新藤優佳、河手久香、田中愛、山内啓弘、村田敏規、新藤隆行
    • Organizer
      第123回日本眼科学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Pathophysiological significance of adrenomedullin-RAMP2 system in age-related macular degeneration2019

    • Author(s)
      Tanaka M, Hirabayashi K, Iesato Y, Imai A, Toriyama Y, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Tanaka M, Yamauchi A, Murata T, Shindo T.
    • Organizer
      The Association for Research in Vision and Ophthalmology (ARVO) 2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] アドレノメデュリン‐RAMP3系の欠損は、癌関連線維芽細胞におけるポドプラニン発現の制御により臓器間転移を抑制する2019

    • Author(s)
      戴昆、田中愛、桜井敬之、神吉昭子、新藤優佳、河手久香、平林一貴、崔南奇、Wei Yangxuan、田中正明、松井周平、中村啓成、新藤隆行
    • Organizer
      第28回日本がん転移学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Loss of adrenomedullin-RAMP3 system suppresses inter-organ metastasis by regulation of podoplanin (PDPN) expression in cancer-associated fibroblasts (CAFs)2019

    • Author(s)
      Dai K, Tanaka M, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Kawate H, Cui N, Wei Y, Matsui S, Nakamura K, Kakihara S, Yamauchi A, Shindo T.
    • Organizer
      第78回日本癌学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] AM-RAMP2系はTGFβ-CXCR4系を抑制し、網膜線維化を抑制する2019

    • Author(s)
      田中正明、平林一貴、今井章、鳥山佑一、家里康弘、桜井敬之、神吉昭子、新藤優佳、河手久香、田中愛、山内啓弘、村田敏規、新藤隆行
    • Organizer
      第73回日本臨床眼科学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] アドレノメデュリン‐RAMP3系欠損は、癌関連線維芽細胞(CAF)の活性を抑制し、癌転移を抑制する2019

    • Author(s)
      戴昆、田中愛、神吉昭子、桜井敬之、新藤優佳、河手久香、崔南奇、Wei Yangxuan、新藤隆行
    • Organizer
      第23回日本心血管内分泌代謝学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 加齢黄斑変性におけるアドレノメデュリン-RAMP系の病態生理学的意義2019

    • Author(s)
      田中正明、柿原伸次、桜井敬之、神吉昭子、市川優佳、田中愛、河手久香、戴昆、村田敏規、新藤隆行
    • Organizer
      第23回日本心血管内分泌代謝学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] アドレノメデュリン-RAMP2系は、筋線維芽細胞分化抑制により、肺線維症の病態を改善する2019

    • Author(s)
      Wei Yangxuan、神吉昭子、桜井敬之、新藤優佳、河手久香、田中愛、戴昆、崔南奇、新藤隆行
    • Organizer
      第23回日本心血管内分泌代謝学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] アドレノメデュリン-RAM2, 3系は、心血管系ストレスに対して、心臓恒常性を制御する2019

    • Author(s)
      崔南奇、神吉昭子、桜井敬之、新藤優佳、河手久香、田中愛、戴昆、Wei Yangxuan、松井周平、新藤隆行
    • Organizer
      第23回日本心血管内分泌代謝学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 脂肪細胞のミトコンドリア機能制御におけるアドレノメデュリン-RAMP2系の病態生理学的意義2019

    • Author(s)
      神吉昭子、桜井敬之、新藤優佳、河手久香、田中愛、田中正明、柿原伸次、松井周平、中村啓成、新藤隆行
    • Organizer
      第23回日本心血管内分泌代謝学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 血管内皮細胞アドレノメデュリンーRAMP2系の、リンパ節転移における病態生理学的意義2019

    • Author(s)
      田中愛、戴昆、桜井敬之、神吉昭子、新藤優佳、河手久香、崔南奇、Wei Yangxuan、田中正明、柿原伸次、松井周平、新藤隆行
    • Organizer
      第27回日本血管生物医学会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 臓器間転移におけるアドレノメデュリン-RAMP系の病態生理学的意義2018

    • Author(s)
      戴昆、田中愛、桜井敬之、神吉昭子、新藤優佳、河手久香、新藤隆行 他
    • Organizer
      第47回日本心脈管作動物質学会
    • Related Report
      2017 Research-status Report
  • [Presentation] アドレノメデュリン-RAMP2系による血管内皮保護機構の解明2017

    • Author(s)
      田中愛、桜井敬之、神吉昭子、新藤優佳、河手久香、新藤隆行 他
    • Organizer
      第21回日本心血管内分泌代謝学会
    • Related Report
      2017 Research-status Report
  • [Presentation] 臓器間転移におけるアドレノメデュリン-RAMP系の病態生理学的意義2017

    • Author(s)
      戴昆、田中愛、桜井敬之、神吉昭子、新藤優佳、河手久香、新藤隆行 他
    • Organizer
      第21回日本心血管内分泌代謝学会
    • Related Report
      2017 Research-status Report
  • [Remarks] 信州大学医学部 循環病態学教室

    • URL

      http://www7a.biglobe.ne.jp/~shindo/

    • Related Report
      2019 Annual Research Report 2017 Research-status Report
  • [Remarks]

    • URL

      http://www7a.biglobe.ne.jp/~shindo/

    • Related Report
      2018 Research-status Report

URL: 

Published: 2017-04-28   Modified: 2021-02-19  

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