Elucidation of pathogenesis for septic encephalopathy based oh new mitochondrial endoplasmic reticulum control pathway

• Project/Area Number: 26462348
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Anesthesiology
• Research Institution: Tokyo Medical University
• Principal Investigator: Uchino Hiroyuki 東京医科大学, 医学部, 主任教授 (60266476)
• Co-Investigator(Kenkyū-buntansha): 諸田 沙織 東京医科大学, 医学部, 助教 (30719711)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
• Keywords: シノビオリン / 敗血症性脳症 / メタボローム / ユビキチンリガーゼ / KAT / キヌレニン / KAT4 / 敗血症 / シノビオリンＫＯマウス / ＣＬＰモデル / 脳内シノビオリン(Syvn) / SyvncKOマウス / 神経細胞死 / 敗血症性脳症(SE) / ERAD

Outline of Final Research Achievements

In this study, we focus on cerebral synoviolin (Syvn) as a ubiquitin ligase (E3) involved in endoplasmic reticulum-related degradation mechanism, the mechanism of septic encephalopathy (SE) was investigated. As a result,1 Metabolome analysis of intracerebral metabolic pathway via Syvn showed a marked decrease in kynurenic acid and a significant increase in kynurenine at 18 hours after SE onset. It became clear that kynurenine plays an important role in inducing the impaiment of the brain. 2 KAT activity by SE was increased, especially, activity of KAT4 significantly increased 18 hours after CLP model creation. Conclusion: Suppression of Syvn and reduction of kinurenine suppresses neuropathy and it may lead to improvement of septic encephalopathy.

Research Products

• [Int'l Joint Research] Lund University, Lund, Sweden(スウェーデン)
• [Journal Article] DIVERSE AND TISSUE-SPECIFIC MITOCHONDRIAL RESPIRATORY RESPONSE IN A MOUSE MODEL OF SEPSIS-INDUCED MULTIPLE ORGAN FAILURE. (2016)
  • Author(s): Karlsson M, Hara N, Morata S, Sjövall F, Kilbaugh T, Hansson MJ, Uchino H, Elmér E.
  • Journal Title: Shock Volume: 45 Issue: 4 Pages: 404-410
  • DOI: 10.1097/shk.0000000000000525
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Metabolomic Analyses of Brain Tissue in Sepsis Induced by Cecal Ligation Reveal Specific Redox Alterations--Protective Effects of the Oxygen Radical Scavenger Edaravone. (2015)
  • Author(s): Hara N, Chijiiwa M, Yara M, Ishida Y, Ogiwara Y, Inazu M, Kuroda M, Karlsson M, Sjovall F, Elmér E, Uchino H.
  • Journal Title: Shock Volume: 44 Issue: 6 Pages: 578-584
  • DOI: 10.1097/shk.0000000000000465
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Molecular mechanisms of ischemic brain damage. (2016)
  • Author(s): Hiroyuki Uchino
  • Organizer: 8th International Federation of Shock Society (IFSS)
  • Place of Presentation: Tokyo
  • Year and Date: 2016-10-03
  • Int'l Joint Research / Invited
• [Presentation] 回盲部結紮穿刺(Cecal Ligation and Puncture;CLP)モデルマウスにおける敗血症関連脳症(Sepsis-associated encephalopathy;SAE)の基礎的解明 (2015)
  • Author(s): 原直美、内野博之
  • Organizer: 日本shock学会
  • Place of Presentation: 八王子
  • Year and Date: 2015-05-22