A Mathematical model of the radiation-induced intercellular-signaling and cell-cycle response

放射線に誘発された細胞間シグナル伝達と細胞周期応答の数理モデルの構築

服部 佑哉; 鈴木 芳代; 舟山 知夫; 小林 泰彦; 横谷 明徳; 渡辺 立子

Hattori, Yuya; Suzuki, Michiyo; Funayama, Tomoo; Kobayashi, Yasuhiko; Yokoya, Akinari; Watanabe, Ritsuko

本研究では、低線量の放射線応答で重要となる細胞間シグナル伝達の動態に着目し、照射する放射線の線量や照射領域によって細胞間シグナル伝達がどのように変化するのか、その動態と細胞周期応答や細胞の生存にはどのような関係性があるのかを明らかにすることを目的とする。そのために、放射線によって誘発された細胞間シグナル伝達と細胞周期応答の時間・空間的な動態を計算可能な数理モデルを構築する。提案する放射線応答モデルでは、細胞集団を格子で分割した2次元平面で表現し、各格子内のシグナル濃度と細胞周期を計算する。細胞間のシグナルは、培養液経由のシグナルX、ギャップ結合経由のシグナルYとし、格子間を拡散方程式に基づいて伝達する。個々の細胞の細胞周期は、周期的な進行(G1, S, G2, M期)がシグナルX, Yによって停止する仮想時計として表現する。モデルを用いて非照射細胞集団のシミュレーションを実施した結果、モデルの細胞周期変化は、実験値をよく再現できた。発表では、さらに、シグナルX, Yを誘発する放射線シグナルZをモデルの特定の細胞に入力後、放射線に誘発されたシグナル伝達の動態と細胞周期応答を計算した一例を示し、放射線応答の解析に対する本モデルの有用性を報告する。

Cell-to-cell communication is one of the important factors to understand the mechanisms of radiation-induced responses such as radiation-induced bystander effects at low doses. However, the involvement of the radiation-induced intercellular-signaling has not been established. In the present study, we propose simulation-based analyses of the intercellular signal transmissions between the individual cells in the cellular population. We modeled the transmissions of two types of signals, i.e., X is transmitted via culture medium and Y is transmitted via gap junctions. The cellular population was described by the grids, and the concentrations of the transmitters, X and Y, were calculated by each grid based on the diffusion equation. To observe the radiation-induced response of the cell caused by the signals, X and Y, we focused on the cell cycle. The cell cycle was modeled as a virtual clock including several check-point pathways and the cyclic process (G1, S, G2, M phases). The signals, X, Y, were transmitted to the cells and stopped the clocks at the check points. In the non-irradiated simulations, the change of cell cycle in our model was similar to that of the experimental data. Furthermore, the radiation was modeled as the radiation signal, Z, which affected the clock and the signals, X and Y. We input the radiation signal, Z, to specific cells, and simulated the behaviors of the clock of each cell and signals, X and Y. We will discuss the radiation-induced damages of the individual cells based on the simulations of the intercellular signaling and the cell cycle.