Novel Techniques for Cell-by-Cell Monte Carlo Simulation of Radiation-Induced DNA Damage and Repair with Models of Specific Chromosome Structures
Author(s)
Andriotty, Matthew
Advisor(s)
Agasthya, Greeshma
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Abstract
New tools have recently been developed to simulate nano-scale radiation track structure and chemical species resulting from the radiolysis of water, record the resulting DNA damage, and model the pathways of DNA repair. These tools allow for in silico investigation of cell radiosensitivity and how it is influenced by several factors, such as the arrangement of chromosomes in the cell nucleus. (1) This work presents a pipeline employing in vitro Hi-C chromosome conformation capture data to create specific cell nucleus models which are then used in TOPAS-nBio radiation simulations. The DSBs are recorded, and then their repair is mechanistically simulated in MEDRAS-MC. This pipeline is used to predict not only the initial radiation-induced DNA damage, but also the repair outcomes resulting from this damage in order to investigate the role chromosome conformation plays in the biological outcome of radiation exposure. (2) This work also establishes a method using libraries of DNA damage files, each consisting of DSB data resulting from a single track of high-LET radiation, to efficiently predict DNA repair outcomes in a variety of scenarios. These libraries are created by running many TOPAS-nBio simulations of a single proton track for a range of energies and recording the DNA damage. A suitable number of these data files are superimposed according to the desired dose, type, and energy of radiation. Then, MEDRAS-MC is used to simulate the repair outcomes of this superimposed radiation damage. These DNA damage data libraries allow for cell-by-cell radiobiological simulation of multiple applications, such as proton or neutron therapy, without the need for time-consuming brute force TOPAS-nBio simulations of high-LET radiation track structure. (3) Additionally, this work demonstrates the incorporation of DNA damage and repair simulations into a larger multiscale framework to simulate the effects of radiation from the whole-body scale to the cellular scale. DNA damage and repair simulations are conducted for individual cells in a multicellular tumor model, and the results are used to calculate linear-quadratic cell-survival curves for the tumor's cells.
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Date
2024-04-27
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Text
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Dissertation