Design of chronotheraputic strategy against tumorgenesis based on modeling of cell cycle interacting with circadian clock

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K00394
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Life / Health / Medical informatics
• Research Institution: Tohoku University
• Principal Investigator: Nakao Mitsuyuki 東北大学, 情報科学研究科, 教授 (20172265)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: 確率オートマトン / 代謝経路選択 / 胆汁酸 / 腸肝循環 / 肝臓ガン

Outline of Final Research Achievements

It has been reported that tumorigenesis and progression increase significantly when the circadian rhythms are impaired. Therefore, the chronotherapy of cancer has naturally been conducted. In this study, we constructed an automaton model of normal and cancer cell proliferation under the control of the circadian clock, and simulated their metabolic selection and proliferation. This indicates that the growth of cancer can be suppressed through metabolic modification. Furthermore, we focused on the transition mechanism from bile acid (BA) concentration abnormality to liver tumorigenesis, and modeling of the control mechanism of BA recycling and production under circadian rhythm control. The modeling indicates that changes in temporal order of BA production/uptake and degradation/excretion could cause an abnormal increase in the hepatic BA concentration, which leads to tumorigenesis.

Free Research Field

生命情報学

Academic Significance and Societal Importance of the Research Achievements

概日時計機構が障害されるとガンの発生率や進行が有意に高まることが知られているが、そのメカニズムは知られていない。本研究では、概日時計の制御を受ける細胞周期確率オートマトンモデルに代謝系を組込み、栄養環境や細胞内概日時計の周期に依存して代謝経路選択や増殖率が異なることを明らかにした。さらに、概日リズム制御下にある肝臓胆汁酸（BA)のリサイクル、産生の制御機構をモデル化し、BA濃度フィードバックシステムが概日時計の変調を受けることによって、生産／取込みと排出の時間的秩序を保ち、それが変容することで異常な濃度上昇が起こり、それがガン化へと至る可能性を示した。これらはガンの時間療法の最適化に役立つ。