Study on the role of endoplasmic reticulum stress in the development of pancreatitis and new treatment through its amelioration

• Project/Area Number: 24591021
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kansai Medical University
• Principal Investigator: AKIYOSHI NISHIO 関西医科大学, 医学部, 准教授 (50362463)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 膵炎 / 小胞体ストレス / アポトーシス / セルレイン / エンドトキシン / 急性膵炎

Outline of Final Research Achievements

To clarify the role of endoplasmic reticulum stress in the development of acute pancreatitis, we created a murine model induced by administration of cerulein and lipopolysaccharide. GRP78 and CHOP proteins increased in the pancreas of mice with pancreatitis. In contrast, administration of an inhibitor of dephosphorylation of eIF2α suppressed pancreatitis, coupled with the increase in phosphorylated eIF2α and ATF4 and the decrease in GRP78 and CHOP protein. Suppression of protein synthesis and increase in ER stress-induced proteins by administration of the inhibitor are supposed to be involved in amelioration of pancreatitis, suggesting the usefulness of augmentation of PERK signaling pathway for the treatment of acute pancreatitis.

Research Products

• [Journal Article] Phosphorylation of Smad2/3 at Specific Linker Threonine Indicates Slow-Cycling Intestinal Stem-Like Cells Before Reentry to Cell Cycle (2015)
  • Author(s): Kishimoto M, Fukui T, Suzuki R, Takahashi Y, Sumimoto K, Okazaki T, Sakao M, Sakaguchi Y, Yoshida K, Uchida K, Nishio A, Matsuzaki K, Okazaki K
  • Journal Title: Digestive Diseases and Sciences Volume: 60 Issue: 2 Pages: 362-374
  • DOI: 10.1007/s10620-014-3348-3
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of neutrophil infiltration between type 1 and type 2 autoimmune pancreatitis. (2015)
  • Author(s): Mitsuyama T, Uchida K, Sumimoto K, Fukui Y, Ikeura T, Fukui T, Nishio A, Shikata N, Uemura Y, Satoi S, Mizuno N, Notohara K, Shimosegawa T, Zamboni G, Frulloni L, Okazaki K.
  • Journal Title: Pancreatology. Volume: Epub ahead of print Issue: 3 Pages: 271-280
  • DOI: 10.1016/j.pan.2015.03.005
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The Role of CD19+CD24highCD38high and CD19+CD24highCD27+ Regulatory B Cells in Patients with Type 1 Autoimmune Pancreatitis. (2014)
  • Author(s): Kimi Sumimoto, Kazushige Uchida, Takeo Kusuda, Toshiyuki Mitsuyama, Yutaku Sakaguchi, Toshiro Fukui, Mitsunobu Matsushita, Makoto Takaoka, Akiyoshi Nishio, Kazuichi Okazaki
  • Journal Title: Pancreatology Volume: in press Issue: 3 Pages: 193-200
  • DOI: 10.1016/j.pan.2014.02.004
  • Peer Reviewed / Open Access
• [Journal Article] Possible involvement of Toll-like receptor 7 in the development of type 1 autoimmune pancreatitis (2014)
  • Author(s): Fukui Y, Uchida K, Sakaguchi Y, Fukui T, Nishio A, Shikata N, Sakaida N, Uemura Y, Satoi S, Okazaki K
  • Journal Title: Journal of Gastroenterology Volume: 50 Issue: 4 Pages: 435-444
  • DOI: 10.1007/s00535-014-0977-4
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Phosphorylation of Smad2/3 at the specific linker threonine residue indicates slow-cycling esophageal stem-like cells before re-entry to the cell cycle (2014)
  • Author(s): Takahashi Y, Fukui T, Kishimoto M, Suzuki R, Mitsuyama T, Sumimoto K, Okazaki T, Sakao M, Sakaguchi Y, Yoshida K, Uchida K, Nishio A, Matsuzaki K, Okazaki K
  • Journal Title: Diseases of the Esophagus Volume: - Issue: 2 Pages: 107-115
  • DOI: 10.1111/dote.12277
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of the dephosphorylation of eukaryotic initiation factor 2α ameliorates murine experimental coliti (2014)
  • Author(s): Okazaki T, Nishio A, Takeo M, Sakaguchi Y, Fukui T, Uchida K, Okazaki K
  • Journal Title: Digestion Volume: 90 Issue: 3 Pages: 167-178
  • DOI: 10.1159/000366414
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Immunoregulatory function of PIR-A/B+ DCs in the inflammatory responses of dextran sodium sulfate-induced colitis (2014)
  • Author(s): Kurishima A, Inaba M, Sakaguchi Y, Fukui T, Uchida K, Nishio A, Nomura S, Okazaki K
  • Journal Title: Journal of Gastroenterology Volume: 49 Issue: 10 Pages: 1367-1377
  • DOI: 10.1007/s00535-013-0879-x
  • Peer Reviewed / Open Access
• [Journal Article] A proposal of a diagnostic algorithm with validation of International Consensus Diagnostic Criteria for autoimmune pancreatitis in a Japanese cohort. (2013)
  • Author(s): Sumimoto K, Uchida K, Mitsuyama T, Fukui Y, Kusuda T, Miyoshi H, Tomiyama T, Fukata N, Koyabu M, Sakaguchi Y, Ikeura T, Shimatani M, Fukui T, Matsushita M, Takaoka M, Nishio A, Okazaki K.
  • Journal Title: Pancreatology. Volume: 13(3) Issue: 3 Pages: 230-7
  • DOI: 10.1016/j.pan.2013.02.010
  • Peer Reviewed
• [Journal Article] Possible Involvement of Foxp3(+) Regulatory T Cells in the Development of Immune-Mediated Pancreatitis in MRL/Mp Mice Treated with Polyinosinic:Polycytidylic Acid. (2013)
  • Author(s): Koyabu M, Uchida K, Sakaguchi Y, Fukata N, Kusuda T, Miyoshi H, Yoshida K, Sumimoto K, Mitsuyama T, Fukui T, Nishio A, Okazaki K.
  • Journal Title: Int J Rheumatol. Volume: 2013 Pages: 367325-30
  • DOI: 10.1155/2013/367325
  • Peer Reviewed
• [Journal Article] The similarity of Type 1 autoimmune pancreatitis to pancreatic ductal adenocarcinoma with significant IgG4-positive plasma cell infiltration. (2013)
  • Author(s): Fukui Y, Uchida K, Sumimoto K, Kusuda T, Miyoshi H, Koyabu M, Ikeura T, Sakaguchi Y, Shimatani M, Fukui T, Matsushita M, Takaoka M, Nishio A, Shikata N, Sakaida N, Uemura Y, Satoi S, Kwon AH, Okazaki K.
  • Journal Title: J Gastroenterol. Volume: 48(6) Issue: 6 Pages: 751-61
  • DOI: 10.1007/s00535-012-0677-x
  • NAID: 10031184065
  • Peer Reviewed
• [Journal Article] Attenuation of indomethacin-induced gastric mucosal injury by prophylactic administration of sake yeast-derived thioredoxin. (2012)
  • Author(s): Nakajima A, et al.
  • Journal Title: J Gastroenterol. Volume: 47 Issue: 9 Pages: 978-987
  • DOI: 10.1007/s00535-012-0564-5
  • Peer Reviewed
• [Journal Article] Comparative Study on Experimental Autoimmune Pancreatitis and Its Extrapancreatic Involvement in Mice. (2012)
  • Author(s): Yamashina M, Nishio A, Nakayama S, Okazaki T, Uchida K, Fukui T, Okazaki K.
  • Journal Title: Pancreas. Volume: 41 Issue: 8 Pages: 1255-62
  • DOI: 10.1097/mpa.0b013e31824a0e58
  • Peer Reviewed
• [Journal Article] Dilatation of the bile and pancreatic ducts due to compression by an unruptured abdominal aortic aneurysm (AAA): a case ameliorated by an endovascular stent grafting (2012)
  • Author(s): Toshiro Fukui
  • Journal Title: Internal Medicine Volume: 51 Pages: 2749-2752
  • Peer Reviewed
• [Presentation] PERKシグナル増強を介したERストレス軽減による実験的大腸炎の改善効果の検討 (2014)
  • Author(s): 岡崎敬、西尾彰功、福井寿朗、内田一茂、岡崎和一
  • Organizer: 第6回日本炎症性腸疾患研究会学術集会
  • Place of Presentation: TKPガーデンシティ品川 （東京都港区）
  • Year and Date: 2014-12-14
• [Presentation] Improvement of endoplasmic reticulum stress by enhanced PERK signaling pathway reduces severe acute pancreatitis in mice (2014)
  • Author(s): Takashi Okazaki, Akiyoshi Nishio, Toshiro Fukui, Kazushige Uchida, Kazuichi Okazaki
  • Organizer: Asian Pacific Digestive Week (APDW) 2014
  • Place of Presentation: Bali Nusa Dua Convention Centre (バリ、インドネシア）
  • Year and Date: 2014-11-24
• [Presentation] Regulatory B Cells in Type 1 Autoimmune Pancreatitis (2014)
  • Author(s): Kimi Sumimoto, Kazushige Uchida, Toshiyuki Mitsuyama, Yuri Fukui, Takeo Kusuda, Hideaki Miyoshi, Norimasa Fukata, Masanori Koyabu, Yutaku Sakaguchi, Tsukasa Ikeura, Masaaki Shimatani, Toshiro Fukui, Mitsunobu Matsushita, Makoto Takaoka, AkiyoshiNishio, Kazuichi Okazaki
  • Organizer: 115th Annual Meeting of the American Gastroenterological Association (DDW2014)
  • Place of Presentation: McCormick Place Chicago Convention Center （米国、シカゴ）
  • Year and Date: 2014-05-03 – 2014-05-06
• [Presentation] Endoplasmic Reticulum Stress Inhibitor Salubrinal protects against Murine Experimental Colitis via the PERK-eIF2α signaling pathway (2013)
  • Author(s): Takashi Okazaki
  • Organizer: 114th Annual Meeting of the American Gastroenterological Association (DDW2013)
  • Place of Presentation: Orland County Convention Center（米国、オーランド）
• [Presentation] Improvement of endoplasmic reticulum stress by enhanced PERK signaling pathway reduces severe acute pancreatitis in mice
  • Author(s): Takashi Okazaki
  • Organizer: 22th United European Gastroenterolgy Week (UEGW2013)
  • Place of Presentation: Internationales Congress Centrum Berlin（ドイツ、ベルリン）
• [Presentation] Endoplasmic Reticulum Stress Inhibitor Salubrinal protects against Murine Experimental Colitis via the PERK-eIF2α signaling pathway
  • Author(s): Takashi Okazaki
  • Organizer: The 1st Annual Meeting of Asian Organization for Crohn’s & Colitis (AOCC)
  • Place of Presentation: ホテルラフォーレ東京（品川）
• [Presentation] Increased peripheral CD19+CD24hiCD38hi regulatory B cells may be involved in the pathology of type 1 autoimmune pancreatitis
  • Author(s): Kimi Sumimoto
  • Organizer: 114th Annual Meeting of the American GAstroenterological Association (DDW2013)
  • Place of Presentation: Orland County Convention Center（米国、オーランド）
• [Presentation] Amelioration of endoplasmic reticulum stress through enhanced PERK signaling attenuates murine experimental colitis
  • Author(s): Takashi Okazaki
  • Organizer: 20th United European Gastroenterology Week
  • Place of Presentation: Amsterdam RAI Exhibition & Convention Centre （オランダ、アムステルダム）
• [Presentation] The specific linker phosphorylation of Smad2/3 indicates epithelial stem cells in esophagus
  • Author(s): Yu Takahashi
  • Organizer: 112th Annual Meeting of the American Gastroenterological Association
  • Place of Presentation: San Diego Convention Center （米国、サンディエゴ）
• [Presentation] Attenuation of indomethacin-induced gastric mucosal injury with prophylactic administration of sake yeast-derived thioredoxin
  • Author(s): Toshiro Fukui
  • Organizer: 112th Annual Meeting of the American Gastroenterological Association
  • Place of Presentation: San Diego Convention Center （米国、サンディエゴ）
• [Presentation] Comparison of International Consensus Diagnostic Criteria and Major Diagnostic Criteria for Autoimmune Pancreatitis
  • Author(s): Kimi Sumimoto
  • Organizer: 112th Annual Meeting of the American Gastroenterological Association
  • Place of Presentation: San Diego Convention Center （米国、サンディエゴ）
• [Presentation] 自己免疫性膵炎マウスにおける膵外病変の比較検討
  • Author(s): 山科 雅央
  • Organizer: 第43回日本膵臓学会大会
  • Place of Presentation: ホテルメトロポリタン山形（山形県）
• [Presentation] アルコール性慢性膵炎の発症における自然免疫/獲得免疫の関与の検討
  • Author(s): 中山 新士
  • Organizer: 第43回日本膵臓学会大会
  • Place of Presentation: ホテルメトロポリタン山形（山形県）
• [Presentation] IgG4関連肝胆膵疾患における制御性T細胞に関する検討
  • Author(s): 内田 一茂
  • Organizer: 第49回日本消化器免疫学会総会
  • Place of Presentation: 城山観光ホテル（鹿児島県）