A Preliminary Study About Radiation Systems Biology

Radiation biology, also known as radiobiology, is a science that involves the study of the action of ionizing radiation and non-ionizing radiation on living things and is important in a lot areas, such as clinical radiation therapy and space radiation protection. In last decades, beyond genome, transcriptome, proteome, the idea of systems biology has been constructed and become a central issue in the field of biology. Generally speaking, systems biology is the computational and mathematical modeling of complex biological systems and is a multidisciplinary including all the omics, informatics and systems science. In systems biology, the biological mechanism is investigated on the systems level by combining the information from genome, transcriptome, proteome or metabolome. The reductionism is replaced by systematology. In this thesis, we investigate mechanisms in irradiated cells by using methods from systems biology and try to make a systematic study. We construct a phenomenological model at the cellular level to explain the dynamics of cell cycle in irradiated 92-1 cells. We make a molecular level study, which is to construct a mathematical model to study the relationship between cell fate after irradiation and the pathway of p53 and p21. It shows that the methods, which are from systems biology, are available in radiation biology.This thesis is divided into four chapters in detail. The summary of each chapter are as follows.Chapter One introduce the background of the radiation systems biology, which contains three parts. The first part contains the definition and content of systems biology. The latest progresses are also introduced. The second part discussed about the radiation biology and the definition of radiation systems biology which is mentioned previously. The third part introduces the mathematical modeling, especially the dynamics modeling.Chapter Two is a research which investigates the dynamics of cell cycle in irradiated 92-1 cells by constructing a phenomenological model and simulating on computers. This model considers the cell cycle arrests at G1 and G2 cell cycle checkpoints. The simulation results of the dynamics of cell cycle in irradiated 92-1 cells are consistent with the experimental results. The relationship between repair times and radiation doses in cells which suffer ionizing radiation is an open question. Our results indicate that the total repair time is proportional to the radiation dose when the there is a high- dose radiation. Moreover, the results indicate that the G1 checkpoint is more stringent than G2 checkpoint, which was mentioned in previous report. The repaired 92-1 cells which have passed G2 checkpoint will still be arrested at G1 point. Compared to previous models of the dynamics of cell cycle, the advantages of our phenomenological model are more simple and a well expansibility.Chapter Three is a research about the cell fate after being irradiated. The mediumterm cell fate after irradiated contains 1)completed repaired and return into cell cycle; 2) long-term arrest; 3) mitosis catastrophe. The final fate contains senescence, apoptosis and autophagy, etc. Based on our experimental data and literature review, it is found that the medium-term cell fate can be related with the pathway of p53-p21. The mathematical model is able to describe the oscillations of expressions of p53 and hdm2 and explain the relationship cell fate and the pathway of p53-p21. From the experimental and calculation results, it indicates that the final fate of long-term arrested cells is senescence while the final fate of mitosis catastrophe cells is senescence or apoptosis.Chapter Four contains three jobs which are about mathematical modeling and molecular evolution. The first is a research about the relationship between mirco RNA-3928 and Dicer protein in irradiated cells. There is a feedback loop between mirco RNA-3928 and Dicer protein in cells. The mature of mirco RNA-3928 needs Dicer but overexpression of mirco RNA-3928 will induce the silence of Dicer. Based on our experimental data, we construct a mathematical model to describe the oscillations of expressions of mirco RNA-3928 and Dicer after being irradiated. The second is a nonlinear fitting of transcriptional regulations in yeast cells by analyzing the timesequencing microarray data in public database. To reduce the fitting errors, we focus on the transcriptional regulation in which the target has only one regulator and the fitting function considers the regulations are time-delayed. The fitting results present the time costs of regulations and the half-lives of some m RNAs. The third is a research about molecular evolution of subunit e in ATP synthase. The function of subunit e is to reinforce the ATP synthase and there is a high homology protein RBF(progesterone receptor binding protein) in avian cells. The cellular location of RBF is the nucleus but not the mitochondria. In the present study, we compared subunit e and RBF in various aspects and demonstrated that two dominant motifs might be the causes of the differences of these two proteins. Motif K(K/R)X(K/R) in mature sequence could help protein enter into the nucleus and deficient of VX2-4D in presequence would block the translocating into mitochondria. These discoveries provide clues for understanding the origin of aves.