Mitochondrial molecular analysis of sepsis-associated encephalopathy by the Cyclophilin D knockout mice

• Project/Area Number: 17K16757
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Anesthesiology
• Research Institution: Tokyo Medical University
• Principal Investigator: UOSHIMA Naomi 東京医科大学, 医学部, 臨床助教 (20792211)
• Project Period (FY): 2017-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 敗血症性脳症 / Cyclophilin D / mitochondria / 敗血症関連脳症 / サイクロフィリンD / 敗血症 / ミトコンドリア / 脳・神経

Outline of Final Research Achievements

Model of sepsis-associated encephalopathy (SAE) were made by cecal ligation and puncture (CLP) using adult male C57/BL6 mice at 7 to 8 weeks of age wild-type (WT mice) mice and mice null for Ppif on the same background (Ppif-/- KO mice). WT mice and KO mice groups were compared mortality rates and cerebral neuronal death by Celestine blue and acid fuchsin staining and HE staining. The mortality rate was significantly lower in KO mice. The expression of inflammatory cytokines and mitochondrial respiratory chain function were measured in the hippocampus and in the cortex at 18 hours after creation of the model, but there were no significant differences. It was not clear whether Cyclophilin D is involved in the pathogenesis of SAE.

Academic Significance and Societal Importance of the Research Achievements

敗血症関連脳症の脳障害発症機序は不明であり標的分子も明らかではない。本研究では活性酸素種により活性化されるBcl family とMPTPを制御するミトコンドリアpeptidyl prolyl isomerase (Ppi）のCyclophilin Dに注目し、SAEの誘発機序としてCyclophilin D遺伝子欠損(Ppif-/-)マウスを用いた盲腸結紮穿孔法誘発脳症モデルにて解析を進めた。死亡率や神経細胞死の減少は認められたが、炎症性サイトカインやミトコンドリア呼吸鎖に有意差はなく詳細なメカニズムの解明には至らなかった。