Molecular mechanism of biological clock alteration by inflammation

• Project/Area Number: 18K10135
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 58040:Forensics medicine-related
• Research Institution: Wakayama Medical University
• Principal Investigator: Kimura Akihiko 和歌山県立医科大学, 医学部, 博士研究員 (60136611)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 体内時計 / 死亡時刻推定法 / 時計遺伝子 / sirtuin1 / Bmal1 / Period / 炎症 / Period 2 / Sirtuin 1 / Sirt1

Outline of Final Research Achievements

Assuming that inflammation may cause modulation of the biological clock, we made a mouse model of cecal ligation and puncture (CLP) for analysis the expression of clock genes in the heart and kidneys. I found that severe inflammation caused by CLP perturbed clock gene expression in the heart and kidney. Since it was known that acetylation is involved in regulation of Bmal1 activity, I analyzed the interaction between the inflammation-activated deacetylase Sirtuin1 and Bmal1 in the CLP model. The results obtained in the present study revealed that Sirtuin1 reduced acetylation of Bmal1 indicating that systemic inflammation modulates the biological clock through deacetylation of Bmal1 by Sirtuin1.

Academic Significance and Societal Importance of the Research Achievements

死亡時刻の推定は法医実務において重要且つ困難な課題であり、世界中の法医学研究者によって様々な方法が報告されているが、現在においても不十分と言わざるを得ない。研究代表者らは体内時計に基づく新規な死亡時刻推定法を確立し実務への応用を進めているが、本法による死亡推定時刻と実際の死亡時刻に齟齬を認める事例を敬遠する。特に重症感染症感染症等の強い炎症を伴う事例ではその頻度が高い。本研究では炎症に伴って活性化する脱acetyl化酵素Sirtuin1により体内時計の駆動機構が摂動を受けることを明らかにした。このことは体内時計に基づく死亡時刻推定法の適用範囲を決定する科学的根拠となる重要な知見と考えている。

Research Products

• [Journal Article] Upregulation of iNOS Protects Cyclic Mechanical Stretch-Induced Cell Death in Rat Aorta Smooth Muscle Cells (2020)
  • Author(s): Zhao Jing、Nakahira Kiichi、Kimura Akihiko、Kyotani Yoji、Yoshizumi Masanori
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 22 Pages: 8660-8660
  • DOI: 10.3390/ijms21228660
  • Peer Reviewed / Open Access
• [Journal Article] Crucial Involvement of IL-6 in Thrombus Resolution in Mice via Macrophage Recruitment and the Induction of Proteolytic Enzymes. (2020)
  • Author(s): Nosaka M, Ishida Y, Kimura A, Kuninaka Y, Taruya A, Ozaki M, Tanaka A, Mukaida N, Kondo T
  • Journal Title: Front Immunol Volume: - Pages: 3150-3150
  • DOI: 10.3389/fimmu.2019.03150
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Forensic pathological study on temporal appearance of dendritic cells in skin wounds. (2020)
  • Author(s): Kuninaka Y, Ishida Y, Nosaka M, Shimada E, Kimura A, Ozaki M, Hata S, Michiue T, Yamamoto H, Furukawa F, Eisenmenger W, Kondo T
  • Journal Title: Int J Legal Med Volume: 134 Issue: 2 Pages: 597-601
  • DOI: 10.1007/s00414-019-02185-z
  • Peer Reviewed / Open Access