Clarification of the mechanism of metabolic and vascular regulation by RAMP and its application in metabolic disorders and vascular injuries.

• Project/Area Number: 20390221
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Shinshu University
• Principal Investigator: SHINDO Takayuki Shinshu University, 医学系研究科, 教授 (90345215)
• Co-Investigator(Kenkyū-buntansha): SAKURAI Takayuki 信州大学, 医学系研究科, 准教授 (80317825) ; SHIMOZAWA Tatsuo 東京大学, 医学部附属病院, 講師 (90231365) ; MURATA Toshinori 信州大学, 医学部, 教授 (50253406)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2010: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2009: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2008: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: アドレノメデュリン / RAMP / 血管 / 動脈硬化 / メタボリックシンドローム / 生活習慣病 / 治療

Research Abstract

Recently, various humoral factors have attracted much attention in terms of being a common molecular basis that links the onset of metabolic syndrome with that of vascular complications. These factors play important roles in the maintenance of metabolic and vascular homeostasis. In contrast, an imbalance between the factors may cause the onset of metabolic syndrome and cardiovascular diseases.
Adrenomedullin (AM), originally identified as a potent vasodilatory peptide produced by vascular cells, has been shown to be synthesized by a variety of cell types and possesses various biological functions. AM has been shown to be involved in both metabolic and vascular homeostasis.
In this study, by using gene-engineered mice of RAMP2 (a receptor activity-modifying protein of AM' s receptor), we proved that RAMP2 is the key molecule of the AM' s metabolic and vascular regulation. RAMP2 could be a novel therapeutic target for metabolic syndrome and cardiovascular diseases.

Research Products

• [Journal Article] Adrenomedullin in sinusoidal endothelial cells play protective roles against cold injury of liver. (2010)
  • Author(s): Iinuma N, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Arai T, Yoshizawa T, Koyama T, Uetake R, Kawate H, Muto S, Tagawa Y, Miyagawa S, Shindo T.
  • Journal Title: Peptides. 31(5) Pages: 865-871
  • NAID: 120007110397
  • Peer Reviewed
• [Journal Article] Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload. (2010)
  • Author(s): Takeda N, Manabe I, Uchino Y, Eguchi K, Matsumoto S, Nishimura S, Shindo T, Nagai R.
  • Journal Title: J Clin Invest. 120(1) Pages: 254-265
  • Peer Reviewed
• [Journal Article] Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overioad.s (2010)
  • Author(s): Takeda N, Manabe I, Uehho Y, EguchiK, Matsumoto S.Nishimura S.Shindo T, et al.
  • Journal Title: J Clin Invest. Volume: 120 Pages: 254-265
  • Peer Reviewed
• [Journal Article] Adrenomedullin in sinusoidal endothelial cells play protective roles against cold injury of liver. (2010)
  • Author(s): Iinuma N, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Arai T, Yoshizawa T, Koyama T, Uetake R, Kawate H, Muto S, Tagawa Y, Miyagawa S, Shindo T
  • Journal Title: Peptides Volume: 31 Pages: 865-871
  • NAID: 120007110397
  • Peer Reviewed
• [Journal Article] Adrenomedullin in sinusoidal endothelial cells play protective roles against cold injury of liver. (2010)
  • Author(s): Iinuma N, Sakurai T, Kamiyoshi A, Ichikawa-Shindo Y, Arai T, Yoshizawa T, Koyama T, Uetake R, Kawate H, Muto S, Tagawa Y, Miyagawa S, Shindo T
  • Journal Title: Peptides. 31(5) Pages: 865-871
  • NAID: 120007110397
  • Peer Reviewed
• [Journal Article] Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload. (2010)
  • Author(s): Takeda N, Manabe I, Uchino Y, Eguchi K, Matsumoto S, Nishimura S, Shindo T, Sano M, Otsu K, Snider P, Conway SJ, Nagai R
  • Journal Title: J Clin Invest. 120(1) Pages: 254-265
  • Peer Reviewed
• [Journal Article] Endogenous a-CGRP mitigates liver fibrosis in chronic hepatitis induced by repeated administration of concanavalin A. (2009)
  • Author(s): Kamiyoshi A, Sakurai T, Ichikawa-Shindo Y, Iinuma N, Kawate H, Yoshizawa T, Koyama T, Muto S, Shindo T.
  • Journal Title: Liver International. 29(5) Pages: 642-649
  • Peer Reviewed
• [Journal Article] Endogenous a-calcitonin gene-related peptide mitigates liver fibrosis in chronic hepatitis induced by repeated administration of concanavalin A (2009)
  • Author(s): Kamiyoshi A, Sakurai T, Shindo Y, Iinuma N, Kawate H, Yoshizawa T, Koyama T, Muto S, Shindo T
  • Journal Title: Liver Int. 29(5) Pages: 642-649
  • Peer Reviewed
• [Journal Article] GPCR modulator protein RAMP2 is essential for angiogenesis and vascular integrity. (2008)
  • Author(s): Ichikawa-Shindo Y, Sakurai T, Kamiyoshi A, Kawate H, Iinuma N, Yoshizawa T, Koyama T, Fukuchi J, Iimuro S, Moriyama N, Kawakami H, Murata T, Kangawa K, Nagai R, Shindo T.
  • Journal Title: J Clin Invest. 118 Pages: 29-39
  • Peer Reviewed
• [Journal Article] Rapid zygosity determination in mice by SYBR Green real-time genomic PCR of a crude DNA solution. (2008)
  • Author(s): Sakurai T, Kamiyoshi A, Watanabe S, Sato M, Shindo T.
  • Journal Title: Transgenic Res. 17 Pages: 149-155
  • Peer Reviewed
• [Journal Article] Crystal structure of the human receptor activity-modifying protein 1 extracellular domain. (2008)
  • Author(s): Kusano S, Kukimoto-Niino M, Akasaka R, Toyama M, Terada T, Shirouzu M, Shindo T, Yokoyama S.
  • Journal Title: Protein Sci. 17(11) Pages: 1907-1914
  • Peer Reviewed
• [Journal Article] Kruppel-like factor 5 causes cartilage degradation through transactivation of matrix metalloproteinase 9. (2008)
  • Author(s): Higashikawa A, Manabe I, Shindo T, Yamada T, Kugimiya F, Ikeda T, Kawamura N, Kawasaki Y, Tsushima K, Takeda N, Nagai R, Hoshi K, Nakamura K, Chung UI, Kawaguchi H.
  • Journal Title: J Biol Chem. 283(36) Pages: 24682-24689
  • Peer Reviewed
• [Journal Article] Crystal structure of the human receptor activity-modifying protein lextracellular domain. (2008)
  • Author(s): Kusano S, Kukimoto-Niino M, Akasaka R, Toyama M, Terada T, Shirouzu M, Shindo T, Yokoyama S.
  • Journal Title: Protein Sci. 17 Pages: 1907-1914
  • Peer Reviewed
• [Journal Article] Kruppel-like factor 5 causes cartilage degradation through transactivation of matrix metalloproteinase 9. (2008)
  • Author(s): Shinoda Y, Ogata N, Higashikawa A, Manabe I, Shindo T, Yamada T, Kugimiya F, Ikeda T, Kawamura N, Kawasaki Y, Tsushima K, Takeda N, Nagai R, Hoshi K, Nakamura K, Chung UI, Kawaguchi H.
  • Journal Title: J Biol Chem. 283 Pages: 24682-24689
  • Peer Reviewed
• [Journal Article] 循環体液調節ペプチド、最近の進歩-アドレノメデュリン受容体の新たな機能 (2008)
  • Author(s): 新藤 隆行
  • Journal Title: 循環器科 64 Pages: 461-467
• [Presentation] Vasoactive peptides and their receptor regulation system. (2010)
  • Author(s): 新藤隆行
  • Organizer: 7th International Symposia on the CGRP
  • Place of Presentation: クイーンズタウン 招待講演
  • Year and Date: 2010-08-29
• [Presentation] RAMP2 is the Key Determinant of the Vascular Functions of Adrenomedullin (2010)
  • Author(s): 新藤隆行
  • Organizer: 7^<th> lntemational Symposia on the CGRP
  • Place of Presentation: オークランド
  • Year and Date: 2010-08-29
• [Presentation] Pathophysiological roles and potential applications of vasoactive peptides and their receptor regulation system. (2010)
  • Author(s): 新藤隆行
  • Organizer: 第28回内分泌代謝学サマーセミナー
  • Place of Presentation: 長崎 招待講演
  • Year and Date: 2010-07-09
• [Presentation] 心脈管作動性物質による臓器保護作用とその応用 (2010)
  • Author(s): 新藤隆行
  • Organizer: 第14回日本神経麻酔・集中治療研究会
  • Place of Presentation: 松本 特別講演
  • Year and Date: 2010-04-24
• [Presentation] 心脈管作動性物質の臓器保護作用とその応用 (2010)
  • Author(s): 新藤隆行
  • Organizer: 第14回日本神経麻酔・集中治療研究会
  • Place of Presentation: 長野
  • Year and Date: 2010-04-24
• [Presentation] RAMP2 is the Key Determinant of the Vascular Functions of Adrenomedullin (2010)
  • Author(s): 新藤隆行
  • Organizer: International Symposium on Cardiovascular Endocrinology and Metabolism
  • Place of Presentation: 奈良 招待講演
  • Year and Date: 2010-04-01
• [Presentation] RAMP2 is the Key Determinant of the Vascular Functions of Adrenomedullin (2010)
  • Author(s): 新藤隆行
  • Organizer: The 14th Scientific Session of the Society of Cardiovascular Endocrinology and Metabolism
  • Place of Presentation: 奈良
  • Year and Date: 2010-04-01
• [Presentation] AM-RAMP2 System, as a Novel Regulator of Cardiac Homeostasis (2010)
  • Author(s): 新藤隆行
  • Organizer: 第74回日本循環器学会
  • Place of Presentation: 京都
  • Year and Date: 2010-03-07
• [Presentation] アドレノメデュリンとその受容体システム (2009)
  • Author(s): 新藤隆行
  • Organizer: 第24回老化促進モデルマウス(SAM)研究協議会
  • Place of Presentation: 松本 特別講演
  • Year and Date: 2009-07-09
• [Presentation] アドレノメデュリン受容体活性調節システムとその病態生理学的意義 (2009)
  • Author(s): 新藤隆行
  • Organizer: 第6回GPCR研究会
  • Place of Presentation: 東京 基調講演
  • Year and Date: 2009-05-08
• [Presentation] アドレノメデュリン受容体活性調節システムとその病態生理学的意義 (2009)
  • Author(s): 新藤隆行
  • Organizer: 第6回CEMフォーラム
  • Place of Presentation: 京都 招待講演
  • Year and Date: 2009-04-04
• [Presentation] 研究最前線心血管作動性物質とその病態生理学的意義 (2009)
  • Author(s): 新藤隆行
  • Organizer: 第16回高血圧・心血管医学内科セミナー
  • Place of Presentation: 前橋 招待講演
  • Year and Date: 2009-02-16
• [Presentation] Receptor activity-modifying protein2 (RAMP2)is essential for angiogenesis and vascular integrity. (2008)
  • Author(s): 新藤 隆行
  • Organizer: American Heart Association 2008
  • Place of Presentation: ニューオーリンズ
  • Year and Date: 2008-11-12
• [Presentation] 発生および病態におけるアドレノメデュリン-RAMPシステムの意義 (2008)
  • Author(s): 新藤隆行
  • Organizer: 第57回福岡心臓血管研究会
  • Place of Presentation: 福岡 招待講演
  • Year and Date: 2008-09-01
• [Presentation] 発生および病態におけるアドレノメデュリン-RAMPシステムの意義 (2008)
  • Author(s): 新藤隆行
  • Organizer: 第1回臨床研究フォーラム招待講演
  • Place of Presentation: 静岡 招待講演
  • Year and Date: 2008-08-08
• [Presentation] Pathophysiological roles of Adrenomedullin-RAMP system in cardiovascular diseases (2008)
  • Author(s): 新藤隆行
  • Organizer: Cardiovascular Expert Forum
  • Place of Presentation: ソウル 招待講演
  • Year and Date: 2008-05-03
• [Remarks] ホームページアドレス
  • URL: http://www7a.biglobe.ne.jp/.shindo/
• [Remarks]
  • URL: http://www7a.biglobe.ne.jP/~shindo/
• [Remarks]
  • URL: http://www7a.biglobe.ne.jp/~shindo/