Development of a new effective therapy of ischemia reperfusion injury of liver and small intestine.

• Project/Area Number: 23591875
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Keio University
• Principal Investigator: SINODA Masahiro 慶應義塾大学, 医学部, 講師 (50286499)
• Co-Investigator(Kenkyū-buntansha): TANABE Minoru 慶應義塾大学, 医学部, 講師(非常勤) (50197513) ; TAKAYANAGI Atsushi 慶應義塾大学, 医学部, 講師 (80245464) ; NISHIYAMA Ryo 慶應義塾大学, 医学部, 助教 (70528322)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: HMGB1 / sRAGE / 肝虚血再灌流 / 肝移植 / 肝細胞移植 / 肝虚血再灌流障害モデル / 移植・再生医療 / ウィルス / 遺伝子 / バイオリアクター

Research Abstract

It is clear that the development of an effective therapy, which would serve as a bridge to liver transplantation or regeneration, is needed to reduce the morbidity and mortality associated with ALF.We paid attention to High-mobility group box1(HMGB1) and sRAGE. HMGB1 has recently been identified as an important mediator of various kinds of acute and chronic inflammation and sRAGE is the soluble receptor of HMGB1.
Although it was difficult to make adenovirus vector which encoded amino acids of sRAGE, we suceeded in making adenovirus vector which encoded amino acids of HMGB1 Box-A protein known to act as a competitive inhibitor of HMGB1.Then,the vector was injcected via the portal vein in rats with acute liver failure.Transfected rats showed decreased hepatic enzymes, plasma HMGB1, and histological findings and survival were significantly improved.

Research Products

• [Journal Article] Hemoadsorption of high-mobility group box chromosomal protein 1 using a column for large animals (2014)
  • Author(s): Nishiyama R, Shinoda M, Tanabe M, Oshima G, Takano K, Miyasho T, Fuchimoto Y, Yamada S, Inoue T, Shimada K, Suda K, Tanaka M, Hayashida T, Yagi H, Kitago M, Obara H, Itano O, Takeuchi H, Kawachi S, Maruyama I, Kitagawa Y
  • Journal Title: Eur Surg Res Volume: 51(3-4) Pages: 181-190
  • Peer Reviewed
• [Journal Article] HMGB1制御による急性肝不全に対する新治療の開発─診療に役立つ治療法の研究─ (2013)
  • Author(s): 篠田昌宏,田邉稔,大島剛,高野公徳,西山亮,田中真之,林田哲,八木洋,阿部雄太,北郷実,田中克典,尾原秀明,板野理,須田康一,竹内裕也,河地茂行,北川雄光
  • Journal Title: 日本腹部救急医学会雑誌 Volume: 33(3) Pages: 535-542
  • NAID: 10031170932
  • Peer Reviewed
• [Journal Article] Neutrophil elastase inhibitor improves survival rate after ischemia reperfusion injury caused by supravisceral aortic clamping in rats (2013)
  • Author(s): Fujimura N, Obara H, Suda K, Takeuchi H, Miyasho T, Kawasako K, Du W, Yamada S, Ono S, Matsumoto K, Matsuda S, Yagi H, Kitago M, Shinoda M, Itano O, Tanabe M, Sakamoto M, Maruyama I, Kitagawa Y
  • Journal Title: J Surg Res Volume: 180(1) Issue: 1 Pages: 31-36
  • DOI: 10.1016/j.jss.2012.04.037
  • Peer Reviewed
• [Journal Article] Hemoadsorption of high-mobility group box chromosomal protein 1 using a column for large animals (2013)
  • Author(s): Nishiyama R, Shinoda M, Tanabe M, Oshima G, Takano K, Miyasho T, Fuchimoto Y, Yamada S, Inoue T, Shimada K, Suda K, Tanaka M, Hayashida T, Yagi H, Kitago M, Obara H, Itano O, Takeuchi H, Kawachi S, Maruyama I, Kitagawa Y
  • Journal Title: Eur Surg Res Volume: 51(3-4) Issue: 3-4 Pages: 181-90
  • DOI: 10.1159/000357563
  • Peer Reviewed / Open Access
• [Journal Article] Increased plasma levels of high mobility group box 1 in patients with acute liver failure (2012)
  • Author(s): Oshima G, Shinoda M, Tanabe M, Ebinuma H, Nishiyama R, Takano K, Yamada S, Miyasho T, Masugi Y, Matsuda S, Suda K, Fukunaga K, Matsubara K, Hibi T, Yagi H, Hayashida T, Yamagishi Y, Obara H, Itano O, Takeuchi H, Kawachi S, Saito H, Hibi T, Maruyama I, Kitagawa Y
  • Journal Title: Eur Surg Res Volume: 48(3) Pages: 154-162
  • Peer Reviewed
• [Journal Article] Role of high mobility group box chromosomal protein 1 in ischemia-reperfusion injury in the rat small intestine (2012)
  • Author(s): Kojima M, Tanabe M, Shinoda M, Yamada S, Miyasho T, Suda K, Hibi T, Obara H, Itano O, Kawachi S, Kitajima M, Maruyama I, Kitagawa Y
  • Journal Title: J Surg Res Volume: 178(1) Issue: 1 Pages: 466-71
  • DOI: 10.1016/j.jss.2012.01.044
  • Peer Reviewed
• [Journal Article] Effect of an omega-3 lipid emulsion in reducing oxidative stress in a rat model of intestinal ischemia-reperfusion injury. (2012)
  • Author(s): Arisue A, Shimojima N, Tomiya M, Shimizu T, Harada D, Nakayama M, Tomita H, Shinoda M, Tanabe M, Maruyama I, Mizuno M, Kuroda T, Wakabayashi G, Morikawa Y.
  • Journal Title: Pediatr Surg Int. Volume: 28 Issue: 9 Pages: 913-918
  • DOI: 10.1007/s00383-012-3144-0
  • Peer Reviewed
• [Journal Article] Alarmin (HMGB1) など―代表的Alarmin, HMGB1研究の今― (2012)
  • Author(s): 篠田昌宏
  • Journal Title: 日本外科感染症学会雑誌 Volume: 9 Pages: 335-341
• [Journal Article] Suppressive effects of Interleukin-18 on liver function in rat liver allografts (2012)
  • Author(s): Ono S
  • Journal Title: J Surg Res Volume: 176 Issue: 1 Pages: 293-300
  • DOI: 10.1016/j.jss.2011.07.053
  • Peer Reviewed
• [Journal Article] Increased plasma levels of high mobility group box 1 in patients with acute liver failure (2012)
  • Author(s): Oshima G, Shinoda M, Tanabe M, Ebinuma H, Nishiyama R, Takano K, Yamada S, Miyasho T, Masugi Y, Matsuda S, Suda K, Fukunaga K, Matsubara K, Hibi T, Yagi H, Hayashida T, Yamagishi Y, Obara H, Itano O, Takeuchi H, Kawachi S, Saito H, Hibi T, Maruyama I, Kitagawa Y
  • Journal Title: Eur Surg Res Volume: 48(3) Issue: 3 Pages: 154-62
  • DOI: 10.1159/000338363
  • Peer Reviewed
• [Journal Article] Pharmacokinetics of mizoribine in adult living donor liver transplantation (2012)
  • Author(s): Shinoda M
  • Journal Title: Transplant Proc Volume: 44 Issue: 5 Pages: 1329-1335
  • DOI: 10.1016/j.transproceed.2012.01.139
  • Peer Reviewed
• [Journal Article] Increased plasma level of High-Mobility Group Box 1 in Acute Liver Failure Patients. (2012)
  • Author(s): Oshima G, Shinoda M, Tanabe M, et al.
  • Journal Title: Eur Surg Res Volume: in press
  • Peer Reviewed
• [Presentation] ラット急性肝不全モデルにおけるHMGB1 A box遺伝子導入の効果 (2014)
  • Author(s): 篠田昌宏
  • Organizer: 第50回日本腹部救急医学会総会
  • Place of Presentation: 東京
• [Presentation] HMGB1に着目した急性肝不全の病態理解と治療法の開発 (2013)
  • Author(s): 篠田昌宏,田中真之,西山亮,大島剛,高野公徳,海老沼浩利,高柳淳,山田晋吾,宮庄拓,須田康一,林田哲,八木洋,阿部雄太,日比泰造,北郷実,尾原秀明,竹内裕也,板野理,丸山征郎,田邉稔,北川雄光
  • Organizer: 第39回日本急性肝不全研究会
  • Place of Presentation: 東京
• [Presentation] HMGB1制御による急性肝不全に対する新治療の開発 (2013)
  • Author(s): 篠田昌宏,田邉稔,田中真之,西山亮,大島剛,高野公徳,海老沼浩利,高柳淳,山田晋吾,宮庄拓,須田康一,林田哲,八木洋,阿部雄太,日比泰造,北郷実,田中克典,尾原秀明,竹内裕也,板野理,丸山征郎,北川雄光
  • Organizer: 第40回日本集中治療医学会学術集会
  • Place of Presentation: 松本
• [Presentation] HMGB1に着目した急性肝不全の病態理解と体外循環吸着療法の可能性 (2013)
  • Author(s): 田中真之, 篠田昌宏, 西山亮, 高野公徳, 高柳淳, 丸山征郎, 田邉稔, 北川雄光
  • Organizer: 第49回日本移植学会総会
  • Place of Presentation: 京都
• [Presentation] HMGB1 A box domainの遺伝子導入方法の確立 (2013)
  • Author(s): 田中真之, 篠田昌宏, 高柳淳, 西山亮, 大島剛, 高野公徳, 山田晋吾, 宮庄拓, 須田康一, 林田哲, 八木洋, 阿部雄太, 日比泰造, 北郷実, 尾原秀明, 竹内裕也, 板野理, 丸山征郎, 田邉稔, 北川雄光
  • Organizer: 第40回日本臓器保存生物医学会学術集会
  • Place of Presentation: 東京
• [Presentation] ラット急性肝不全モデルにおけるHMGB1 A box遺伝子導入の効果 (2013)
  • Author(s): 雨宮隆介, 篠田昌宏, 田中真之, 高柳淳, 西山亮, 大島剛, 山田晋吾, 宮庄拓, 須田康一, 八木洋, 林田哲, 阿部雄太, 日比泰造, 北郷実, 尾原秀明, 竹内裕也, 板野理, 丸山征郎, 田邉稔, 北川雄光
  • Organizer: 第20回外科侵襲とサイトカイン研究会
  • Place of Presentation: 渋川
• [Presentation] 急性肝不全患者におけるHMGB1動態と動物モデルにおけるHMGB1制御の効果 (2012)
  • Author(s): 篠田昌宏,田邉稔,高野公徳,大島剛,西山亮,海老沼浩利,高柳淳,山田晋吾,宮庄拓,松原健太郎,須田康一,林田哲,八木洋,尾原秀明,竹内裕也,板野理,河地茂行,斉藤英胤,日比紀文,丸山征郎,北川雄光
  • Organizer: 第112回日本外科学会定期学術集会
  • Place of Presentation: 幕張
• [Presentation] HMGB1 A box遺伝子導入ベクタ-の樹立とラット急性肝不全モデルにおける予後改善効果 (2012)
  • Author(s): 篠田昌宏,田邉稔,西山亮,高柳淳,大島剛,田中真之,山田晋吾,宮庄拓,須田康一,松原健太郎,八木洋,林田哲,北郷実,尾原秀明,竹内裕也,板野理,福永興壱,河地茂行,丸山征朗,北川雄光
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 東京
• [Presentation] HMGB1阻害タンパクA boxの遺伝子導入ベクタ-の確立とラット急性肝不全モデルにおける予後改善効果 (2012)
  • Author(s): 篠田昌宏,田邉稔,西山亮,高柳淳,大島剛,田中真之,山田晋吾,宮庄拓,須田康一,福永興壱,八木洋,林田哲,松原健太郎,北郷実,尾原秀明,竹内裕也,板野理,河地茂行,丸山征朗,北川雄光
  • Organizer: 第48回日本腹部救急医学会総会
  • Place of Presentation: 金沢
• [Presentation] Gene Transfer of the A box domain of HMGB1 into the Liver in rat acute liver failure model (2011)
  • Author(s): Shinoda M, Tanabe M, Nishiyama R, Takayanagi A, Oshima G, Takano K, Yagi H, Kawachi S, Maruyama I, Kitagawa Y
  • Organizer: 97th American College of Surgeons Clinical Congress
  • Place of Presentation: San Francisco
• [Presentation] HMGB1制御による急性肝不全に対する新治療の開発～診療に役立つ治療法の研究～ (2011)
  • Author(s): 篠田昌宏,田邉稔,高野公徳,大島剛,西山亮,海老沼浩利,山田晋吾,宮庄拓,須田康一,竹内裕也,板野理,河地茂行,齋藤英胤,丸山征郎,日比紀文,北川雄光
  • Organizer: 第47回日本腹部救急医学会総会
  • Place of Presentation: 福岡
• [Presentation] Hemoadsorption of High-Mobility Group Box 1 in swine acute liver failure model. (2011)
  • Author(s): Nishiyama R, Shinoda M, tanabe M et, et al.
  • Organizer: ASAIO 57th Annual Conference
  • Place of Presentation: Washington, DC
• [Presentation] Gene Transfer of the High Mobility Group Box 1 Inhibitor in Rat Acute Liver Failure Model. (2011)
  • Author(s): Shinoda M, Tanabe M, Takayanagi A, et al.
  • Organizer: The 2011 Joint International Congress of ILTS, ELITA, & LICAGE
  • Place of Presentation: Valencia
• [Presentation] Hemoadsorption of high-mobility group box 1 in swine acute liver failure model. (2011)
  • Author(s): Nishiyama R, Shinoda M, Tanabe M, et al.
  • Organizer: International Surgical Week ISW 2011
  • Place of Presentation: Pacifico Yokohama（神奈川）
• [Presentation] Gene Transfer of the A box domain of HMGB1 into the Liver in rat acute liver failure model. (2011)
  • Author(s): Shinoda M, Tanabe M, Nishiyama R, et al.
  • Organizer: 97th American College of Surgeons Clinical Congress
  • Place of Presentation: San Francisco
• [Presentation] Establishment of rat hepatocyte producing high mobility group box 1 inhibitor. (2011)
  • Author(s): Shinoda M, Nishiyama R, Tanabe M, et al.
  • Organizer: XXXVIII Congress of the European Society for Artificial Organs (ESAO 2011) and IV Biennial Congress of the International Federation on Artificial Organs (IFAO 2011)
  • Place of Presentation: Portugal
• [Presentation] 急性肝不全患者におけるHMGB1動態と動物モデルにおけるHMGB1制御の効果
  • Author(s): 篠田昌宏
  • Organizer: 第112回日本外科学会定期学術集会
  • Place of Presentation: 幕張
• [Presentation] HMGB1 A box遺伝子導入ベクターの樹立とラット急性肝不全モデルにおける予後改善効果
  • Author(s): 篠田昌宏
  • Organizer: 第98回日本消化器病学会総会
  • Place of Presentation: 東京
• [Presentation] MGB1阻害タンパクA boxの遺伝子導入ベクターの確立とラット急性肝不全モデルにおける予後改善効果
  • Author(s): 田中真之
  • Organizer: 第27回日本Shock学会総会
  • Place of Presentation: 東京
• [Presentation] Hemoadsorption of high-mobility group box 1 in swine acute liver failure model
  • Author(s): Shinoda M
  • Organizer: American Transplant Congress 2012
  • Place of Presentation: Boston
• [Presentation] ラット急性肝不全モデルにおけるHMGB1 A box domainの肝への遺伝子導入とその効果
  • Author(s): 田中真之
  • Organizer: 第38回日本急性肝不全研究会
  • Place of Presentation: 金沢
• [Presentation] "ブタ急性肝不全モデルにおけるHigh mobility group box-1 吸着カラムの有用性の 検討"
  • Author(s): 篠田昌宏
  • Organizer: 第30回日本肝移植研究会
  • Place of Presentation: 福岡
• [Presentation] Hemoadsorption of high-mobility group box 1 in swine acute liver failure mdoel
  • Author(s): Shinoda M
  • Organizer: 10th World Congress of the International Hepato-Pancreato-Biliary Association
  • Place of Presentation: Paris
• [Presentation] Gene transfer of the A box domain of high mobility group box 1 into the liver in rat acute liver failure model
  • Author(s): Shinoda M
  • Organizer: 10th World Congress of the International Hepato-Pancreato-Biliary Association
  • Place of Presentation: Paris
• [Presentation] 薬剤誘導性ラット劇症肝不全モデルの作成～DHLHISZnの病態改善効果検討へ向けて～
  • Author(s): 田中真之
  • Organizer: 第3回癌・炎症とαリポ酸研究会
  • Place of Presentation: 由布
• [Presentation] Gene transfer of A Box domain of High Mobility Group Box 1 in rat acute liver failure model
  • Author(s): Tanaka M
  • Organizer: The 63rd Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Boston
• [Presentation] Hemoadsorption of high-mobility group box 1 in a swine acute liver failure model
  • Author(s): Shinoda M
  • Organizer: The 63rd Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Boston
• [Presentation] HMGB1制御による急性肝不全に対する新治療の開発
  • Author(s): 篠田昌宏
  • Organizer: 第40回日本集中治療医学会学術集会
  • Place of Presentation: 松本
• [Presentation] 急性肝不全におけるHigh mobility group box-1吸着療法の基礎的検討
  • Author(s): 篠田昌宏
  • Organizer: 第49回日本腹部救急医学会総会
  • Place of Presentation: 福岡
• [Presentation] High mobility group box-1に着目した急性肝不全治療の基礎的検討
  • Author(s): 篠田昌宏
  • Organizer: 第99回日本消化器病学会総会
  • Place of Presentation: 鹿児島
• [Book] 慶應義塾大学における急性肝不全に対する成人ABO血液型不適合生体肝移植. ABO血液型不適合移植の新戦略―2013―, In :高橋公太,田中紘一Eds, 1Ed (2013)
  • Author(s): 篠田昌宏,田邉稔,板野理,尾原秀明,北郷実,田中克典,阿部雄太,八木洋,日比泰造,藤野明浩,下島直樹,星野健,黒田達夫,北川雄光
  • Publisher: 日本医学館,東京
• [Patent(Industrial Property Rights)] ハイモビリティーグループタンパク吸着担体 (2011)
  • Inventor(s): 島田薫，井上武大，北川雄光，篠田昌宏，田邉稔，西山亮
  • Industrial Property Rights Holder: 島田薫，井上武大，北川雄光，篠田昌宏，田邉稔，西山亮
  • Filing Date: 2011
  • Acquisition Date: 2012