Novel methods to regulate hepatic graft by extracorporial perfusion : Chaperoen mediated mechanisms

• Project/Area Number: 26670572
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General surgery
• Research Institution: Hokkaido University
• Principal Investigator: Shimamura Tsuyoshi 北海道大学, 大学病院, 准教授 (00333617)
• Co-Investigator(Kenkyū-buntansha): 深井 原 北海道大学, 医学研究科, 特任助教 (60374344) ; 木村 太一 北海道大学, 医学研究科, 特任助教 (90435959)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 移植・再生医療 / 外科 / 発現制御 / 臓器灌流 / 虚血再灌流 / 臓器保存 / 抗酸化 / 肝移植 / 脂肪肝 / シャペロン

Outline of Final Research Achievements

The role of 14-3-3 zeta on the cellular injury and energy production during and after hypothermic storage with or without oxygen, using mouse hepatocytes derived cell line (AML12). 14-3-3 zeta overexpression was introduced by gene delivery or some small molecule. After confirmation of 14-3-3 zeta protein level, cells were subjected to hypothermic oxygenate condition mimicking the cellular environment during organ perfusion. Combination of 14-3-3 zeta inducing molecule and hydrogen sulfide strengthen the mitochondrial functions related to oxidative phosphorylation, drug (MTT) metabolism, and antioxidant ability, due to the prevention of protein dephosphorylation (14-3-3) and stimulation of ARE-binding transcription factors (NaHS). These results revealed novel strategy to pre-condition the marginal graft not by gene delivery but by transcriptional and post-translational regulations.

Research Products

• [Journal Article] Hydrogen Gas Ameliorates Hepatic Reperfusion Injury After Prolonged Cold Preservation in Isolated Perfused Rat Liver (2016)
  • Author(s): Shimada S, Wakayama K, Fukai M, Shimamura T, Ishikawa T, Fukumori D, Shibata M, Yamashita K, Kimura T, Todo S, Ohsawa I, Taketomi A
  • Journal Title: Artif Organs Volume: 40 Issue: 12 Pages: 1128-1136
  • DOI: 10.1111/aor.12710
  • Peer Reviewed
• [Journal Article] 14-3-3ζ-mediated stimulation of oxidative phosphorylation exacerbates oxidative damage under hypothermic oxygenated conditions in human renal tubular cells (HK-2) (2016)
  • Author(s): Fukai M, Kobayashi N, Ishikawa T, Wakayama K, Shimada S, Umemoto K, Ohtani S, MFujiyoshi M, Yamashita K, Shimamura T, Taketomi A
  • Journal Title: Transplant Proc. Volume: 48 Issue: 4 Pages: 1288-1291
  • DOI: 10.1016/j.transproceed.2015.09.066
  • Peer Reviewed
• [Journal Article] Significance of regulating protein functions under hypothermic oxygenated conditions (2016)
  • Author(s): 深井原，島田慎吾, 小林希、石川隆壽、梅本浩平、大谷晋太郎、山下健一郎、嶋村剛、武冨紹信
  • Journal Title: Organ Biology Volume: 23 Issue: 2 Pages: 173-179
  • DOI: 10.11378/organbio.23.173
  • NAID: 130005263592
  • ISSN: 1340-5152, 2188-0204
• [Journal Article] A pilot study of operational tolerance with a regulatory T cell-based cell therapy in living donor liver transplantation. (2016)
  • Author(s): ①Todo S, Yamashita K, Goto R, Zaitsu M, Nagatsu A, Oura T, Watanabe M, Aoyagi T, Suzuki T, Shimamura T, Kamiyama T, Sato N, Sugita J, Hatanaka K, Bashuda H, Habu S, Demetris AJ, Okumura K
  • Journal Title: Hepatology Volume: 00 Issue: 2 Pages: 00-00
  • DOI: 10.1002/hep.28459
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 北海道の地域連携からドナー獲得への取り組みは成功したのか (2016)
  • Author(s): 嶋村 剛、古川博之、藤堂 省
  • Journal Title: 肝胆膵 Volume: 72 Pages: 453-461
• [Journal Article] 14-3-3ζ-mediated stimulation of oxidative phosphorylation exacerbates oxidative damage under hypothermic oxygenated conditions in human renal tubular cells (HK-2) (2016)
  • Author(s): Moto Fukai, Nozomi Kobayashi, Takahisa Ishikawa, Kenji Wakayama, Shingo Shimada, Kohei Umemoto, Shintaro Ohtani, Masato Fujiyoshi, Kenichiro Yamashita, Tsuyoshi Shimamura, and Akinobu Taketomi
  • Journal Title: Transplantation Proceedings Volume: in press
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hydrogen sulfide augments survival signals in warm ischemia and reperfusion of the mouse liver. (2015)
  • Author(s): Shimada S, Fukai M, Wakayama K, Ishikawa T, Kobayashi N, Kimura T, Yamashita K, Kamiyama T, Shimamura T, Taketomi A, Todo S
  • Journal Title: Surg Today Volume: 45 Pages: 892-903
  • Peer Reviewed
• [Journal Article] A Nationwide Survey of Hepatitis E Virus Infection and Chronic Hepatitis E in Liver Transplant Recipients in Japan (2015)
  • Author(s): Yuki Inagaki, Yukio Oshiro,Tsuyoshi Shimamura,Nobuhiro Ohkohchi
  • Journal Title: EBioMedicine Volume: 2 Pages: 1607-1612
  • NAID: 120005980821
  • Peer Reviewed
• [Journal Article] Multicentre, randomised, placebo-controlled trial of extract of Japanese herbal medicine Daikenchuto to prevent bowel dysfunction after adult liver transplantation (DKB 14 Study). (2015)
  • Author(s): Kaido T, Shimamura T, Sugawara Y, Sadamori H, Shirabe K, Yamamoto M, Uemoto S
  • Journal Title: BMJ Open Volume: 5
  • NAID: 120005820862
  • Peer Reviewed
• [Journal Article] 肝移植 (2015)
  • Author(s): 嶋村 剛、藤堂 省
  • Journal Title: 消化器外科 Volume: 38 Pages: 921-930
• [Journal Article] 臓器保存におけるオートファジーの病態と評価法 (2015)
  • Author(s): 深井原，島田慎吾, 若山顕治, 石川隆壽、嶋村剛, 山下健一郎, 武冨紹信
  • Journal Title: Organ Biology Volume: 22 Pages: 26-31
  • NAID: 130005142913
• [Journal Article] Hydrogen sulfide augments survival signals in warm ischemia and reperfusion of the mouse liver. (2015)
  • Author(s): Shimada, S., Fukai, M., Wakayama, K., Ishikawa, T., Kobayashi, N., Kimura, T., Yamashita, K., Kamiyama, T., Shimamura, T., Taketomi, A., Todo, S.
  • Journal Title: Surgery Today Volume: 45 Issue: 7 Pages: 892-903
  • DOI: 10.1007/s00595-014-1064-4
  • Peer Reviewed / Open Access
• [Journal Article] APRV in patients with atelectasis after liver transplantation. (2014)
  • Author(s): Nakahashi S, Furukawa H, Shimamura T, Todo S, Gando S:
  • Journal Title: Anaesth Intensive Care Volume: 42(1) Pages: 138-140
  • Peer Reviewed
• [Journal Article] A technique for orthotopic liver transplantation in cynomolgus monkeys. (2014)
  • Author(s): Tetsu Oura, Kenichiro Yamashita, Tomomi Suzuki, Masaaki Watanabe, Gentaro Hirokata, Kenji Wakayama, Masahiko Taniguchi, Tsuyoshi Shimamura, Hiroyuki Furukawa and Satoru Todo
  • Journal Title: Transplantation Volume: 98(6)
  • Peer Reviewed
• [Journal Article] Small-for-size syndrome in living-donor liver transplantation using a left lobe graft. (2014)
  • Author(s): Taniguchi M, Shimamura T, Todo S, Furukawa H
  • Journal Title: Surgery Today Volume: epub Issue: 6 Pages: 663-671
  • DOI: 10.1007/s00595-014-0945-x
  • Peer Reviewed
• [Journal Article] Establishment of educational program for multiorgan procurement from deseased donors. (2014)
  • Author(s): Taniguchi M, Furukawa H, Kawai T, Morikawa H, Morozumi K, Goto M, Kondo T, Aikawa A, Ito T, Takahara S, Nio M, Kokudo N, Uemoto S, Fukushima N, Yoshida K, Kenmochi T, Date H, Ono M, Eguchi S, Shimamura T, Mizuta K, Yoshizumi T, Ueno T
  • Journal Title: Transplant Proc Volume: 46 Pages: 1071-1073
  • Peer Reviewed
• [Journal Article] 薬物性劇症肝不全に対する肝移植． (2014)
  • Author(s): 嶋村 剛、太田 稔、山下健一郎
  • Journal Title: 肝胆膵 Volume: 68(2)
  • Peer Reviewed
• [Journal Article] 肝癌移植症例におけるABO血液型不適合脱感作療法のインパクト． (2014)
  • Author(s): 江川裕人、嶋村 剛、藤堂 省
  • Journal Title: 日本消化器病学会雑誌 Volume: 111(5) Pages: 892-898
  • NAID: 130004448896
  • Peer Reviewed
• [Journal Article] 肝癌． (2014)
  • Author(s): 柿坂達彦、神山俊哉、若山顕治、横尾英樹、折茂達也、敦賀陽介、蒲池浩文、山下健一郎、嶋村 剛、武冨紹信
  • Journal Title: 臨床外科 Volume: 69(12)
  • Peer Reviewed
• [Presentation] イメージング質量分析 (IMS)による阻血再灌流における新規予後予測マーカーの探索 (2017)
  • Author(s): 橋本咲月、深井原、梅本浩平、木村太一、大谷晋太郎、中薮拓哉、早坂孝宏、三野和宏、惠淑萍、千葉仁志、嶋村剛、武冨紹信
  • Organizer: 第29回 代用臓器・再生医学研究会
  • Place of Presentation: かでる２・７（北海道札幌市）
  • Year and Date: 2017-02-25
• [Presentation] 臓器灌流法の先にあるべき技術の開発 (2016)
  • Author(s): 深井原，島田慎吾，小林希，梅本浩平， 大谷晋太郎 ，中薮拓哉，三野和宏， 山下健一郎，嶋村剛，武冨紹信
  • Organizer: 第43回 日本臓器保存生物医学会学術集会
  • Place of Presentation: 東京薬科大学（東京都八王子市）
  • Year and Date: 2016-11-26
• [Presentation] 北海道における肝移植：過去・現在・未来 (2016)
  • Author(s): 嶋村剛
  • Organizer: 第6回 Trans-ARIAKE Liver Transplantation Forum
  • Place of Presentation: 熊本大学医学部付属病院 山崎記念館（熊本県熊本市）
  • Year and Date: 2016-10-08
  • Invited
• [Presentation] イメージング質量分析によるラット脂肪肝虚血再灌流障害の評価 (2016)
  • Author(s): 橋本咲月、深井原、早坂孝宏、梅本浩平、大谷晋太郎、白澤憲典、中薮拓哉、島田慎吾、惠淑萍、千葉仁志、山下健一郎、嶋村剛、武冨紹信
  • Organizer: 第34回 日本肝移植研究会
  • Place of Presentation: 大雪アリーナホール（北海道旭川市）
  • Year and Date: 2016-07-07
• [Presentation] 脳死肝移植を増やすために今できること：北海道における臓器提供・移植医療の理解に向けた取り組み (2016)
  • Author(s): 嶋村剛、古川博之、藤堂省
  • Organizer: 第34回 日本肝移植研究会
  • Place of Presentation: 大雪アリーナホール（北海道旭川市）
  • Year and Date: 2016-07-07
• [Presentation] 肝細胞癌に対する生体肝移植：全国集計 (2016)
  • Author(s): 嶋村剛
  • Organizer: 第34回 日本肝移植研究会
  • Place of Presentation: 大雪アリーナホール（北海道旭川市）
  • Year and Date: 2016-07-07
• [Presentation] 低温酸素化状態における14-3-3zetaによるエネルギー産生と細胞内シグナルの制御－ヒト尿細管上皮細胞株 (HK2) を用いた検討 (2016)
  • Author(s): 深井原、小林希、梅本浩平、島田慎吾、若山顕治、大谷晋太郎、橋本咲月、藤好真人、山下健一郎、嶋村剛、武冨紹信
  • Organizer: 第116回 日本外科学会定期学術集会
  • Place of Presentation: リーガロイヤルホテル大阪（大阪府大阪市）
  • Year and Date: 2016-04-16
• [Presentation] ラット肝冷保存再灌流における重水含有臓器液 (Dsol) の保護効果～Autophagyと細胞生存・死シグナルへの影響 (2016)
  • Author(s): 梅本浩平、深井原、島田慎吾、石川隆壽、大谷晋太郎、橋本咲月、藤好真人、若山顕治、山下健一郎、嶋村剛、武冨紹信
  • Organizer: 第116回 日本外科学会定期学術集会
  • Place of Presentation: リーガロイヤルホテル大阪（大阪府大阪市）
  • Year and Date: 2016-04-16
• [Presentation] 心臓死ドナーグラフトにおける水素ガスの肝保護効果の検討 (2016)
  • Author(s): 石川隆壽、深井原、若山顕治、島田慎吾、梅本浩平、藤好真人、山下健一郎、嶋村剛、武冨紹信
  • Organizer: 第116回 日本外科学会定期学術集会
  • Place of Presentation: リーガロイヤルホテル大阪（大阪府大阪市）
  • Year and Date: 2016-04-16
• [Presentation] Time course of autophagy and oxidative phosphorylation during hypothermic oxygenated conditions and subsequent re-warming in human renal tubular cell line (HK2). (2016)
  • Author(s): Fukai M, Ishikawa T, Wakayama K, Shimada S, Fujiyoshi M, Kimura T, Yamashita K, Shimamura T, Taketomi A
  • Organizer: Transplantation Science Symposium Asian Regional Meeting 2016 (TSS)
  • Place of Presentation: KFC Hall（Tokyo, Japan）
  • Year and Date: 2016-04-08
  • Int'l Joint Research
• [Presentation] 臓器移植の発展と解決すべき問題点：改正臓器移植法が肝移植に及ぼした影響と推進に向けた活動 (2015)
  • Author(s): 嶋村剛
  • Organizer: 第77回 日本臨床外科学会総会
  • Place of Presentation: 福岡国際会議場（福岡県福岡市）
  • Year and Date: 2015-11-27
• [Presentation] 低温灌流時の酸化的リン酸化と細胞内シグナルの制御～尿細管上皮を用いた検討 (2015)
  • Author(s): 深井原、島田慎吾、若山顕治、石川隆壽、山下健一郎、嶋村剛、武冨紹信
  • Organizer: 第42回 日本臓器保存生物医学会学術集会
  • Place of Presentation: いわて県民情報交流センター（岩手県盛岡市）
  • Year and Date: 2015-11-13
  • Invited
• [Presentation] Time course of autophagy and oxidative phosphorylation dering hypothermic oxygenated conditions and subsequent re-warming in human renal tubular cell line (HK2) (2015)
  • Author(s): Fukai M, Ishikawa T, Wakayama K, Shimada S, Fujiyoshi M, Kimura T, Yamashita K, Shimamura T, Taketomi A
  • Organizer: Congress of the European Society for Organ Transplantation (ESOT)
  • Place of Presentation: SQUARE BRUSSELS MEETING CENTRE (Brussels Belgium)
  • Year and Date: 2015-09-14
  • Int'l Joint Research
• [Presentation] 肝細胞癌に対する肝移植 全国集計結果から見えてきたもの (2015)
  • Author(s): 嶋村剛
  • Organizer: 第11回 広島臓器移植セミナー
  • Place of Presentation: 広島大学病院（広島県広島市）
  • Year and Date: 2015-09-04
  • Invited
• [Presentation] Signal transduction during hypothermic oxygenated conditions in human renal tubular cells. (2015)
  • Author(s): Fukai M, Ishikawa T, Wakayama K, Shimada S, Kimura T, Yamashita K, Shimamura T, Taketomi A
  • Organizer: Congress of the Asian Society of Transplantation (CAST)
  • Place of Presentation: Suntec Singapore Convention&Exhibition Centre (Suntec City,Singapore)
  • Year and Date: 2015-08-25
  • Int'l Joint Research
• [Presentation] トリアゾロピリミジン化合物NK026680(による抗原特異的制御性T細胞誘導効果 (2015)
  • Author(s): 後藤了一、柴崎晋、長津明久、小野仁、五十嵐瑠美、深井原、嶋村剛、雑賀寛、武冨紹信、藤堂省、山下健一郎
  • Organizer: 第115回 日本外科学会定期学術集会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-04-18
• [Presentation] 低温酸素化体外灌流における水素ガスの肝保護効果 (2015)
  • Author(s): 石川隆壽、深井原、島田慎吾、若山顕治、後藤了一、木村太一、大澤郁朗、山下健一郎、嶋村剛、武冨紹信
  • Organizer: 第115回 日本外科学会定期学術集会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-04-17
• [Presentation] 改正臓器移植法が肝移植に及ぼした影響と推進に向けた現状での次善策、今後の改善策について (2015)
  • Author(s): 嶋村剛
  • Organizer: 第115回 日本外科学会定期学術集会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-04-17
• [Presentation] 肝細胞癌に対する肝移植適応‐全国集計をもとに‐ (2014)
  • Author(s): 嶋村 剛
  • Organizer: 第32回日本肝移植研究会
  • Place of Presentation: 京王プラザホテル (東京都)
  • Year and Date: 2014-07-04
• [Presentation] 一般演題7 生体ドナー (2014)
  • Author(s): 嶋村 剛
  • Organizer: 第32回日本肝移植研究会
  • Place of Presentation: 京王プラザホテル (東京都)
  • Year and Date: 2014-07-03
• [Presentation] 成人間生体肝移植における術後短期の予後予測 (2014)
  • Author(s): 嶋村 剛
  • Organizer: 第26回日本肝胆膵外科学会学術集会
  • Place of Presentation: 和歌山県民文化会館 (和歌山市)
  • Year and Date: 2014-06-13
• [Presentation] Successful Withdrawal of Immunosuppression by a Cell Therapy Using Donor Ag-pulsed Tregs in Living Donor Liver Transplantation: An Update on Clinical Trial. (2014)
  • Author(s): Kenichiro Yamashita, Masaki Zaitsu, Akihisa Nagatsu, Ryoichi Goto, Tetsu Oura, Masaaki Watanabe, Takeshi Aoyagi, Tomomi Suzuki, Tsuyoshi Shimamura, Toshiya Kamiyama, Norihiro Sato, Junichi Sugita, Kanako Hatanaka, Hisashi Bashuda, Ko Okumura, Satoru Todo
  • Organizer: The 2014 Joint International Congress of ILTS, ELITA & LICAGE
  • Place of Presentation: Queen Elizabeth II Conference Centre (London, UK)
  • Year and Date: 2014-06-04 – 2014-06-07
• [Presentation] Preoperative Prediction of Short-Term Prognosis after Adult-to-Adult Living Donor Liver Transplantation: A Way to Zero-Mortality. (2014)
  • Author(s): Tsuyoshi Shimamura, Masato Fujiyoshi, Tomomi Suzuki, Kenichiro Yamashita, Takeshi Aoyagi, Ryoichi Goto, Toru Takahashi, Yasuyuki Koshizuka, Masahiko Taniguchi, Hiroyuki Furukawa, Satoru Todo
  • Organizer: The 2014 Joint International Congress of ILTS, ELITA & LICAGE
  • Place of Presentation: Queen Elizabeth II Conference Centre (London, UK)
  • Year and Date: 2014-06-04 – 2014-06-07
• [Presentation] ワークショップ1 人工肝 (2014)
  • Author(s): 嶋村 剛
  • Organizer: 第40回日本急性肝不全研究会
  • Place of Presentation: ホテルニューオータニ (東京都)
  • Year and Date: 2014-05-28
• [Presentation] 移植医療の現状と臨床検査のかかわり (2014)
  • Author(s): 嶋村 剛
  • Organizer: 北海道シーメンスフォーラム2014
  • Place of Presentation: ホテルポールスター札幌 (札幌市)
  • Year and Date: 2014-05-24