? The main objective of this project is the development of a computational multi-scale model of carcinogenesis that spans spatial and temporal scales from the level of the cell to the level of the human population. Specifically, it includes the modular development of a multiscale and multistage carcinogenesis simulation model that consists of three major components: From a cell to a proliferative unit module. Checkpoint delays, repair processes, and the apoptotic sensitivity of stem cells are assumed optimized to delay the process of neoplastic progression. This 'optimization' problem will be addressed by both deterministic and stochastic descriptions of stem cell population homeostasis in a proliferative unit (crypt). From a proliferative unit to a tissue module. Mechanisms that disrupt tissue architecture and allow neoplastic clones to expand may generate distinct spatial distributions of genetic lesions. The multiscale model developed here will be used to explore the spatial and genetic patterns of clones produced by crypt bifurcations, epithelial restitution and cell migration with or without wound healing. From a tissue to a population module. The micro-simulation model at the tissue level will be employed to derive first-passage-times for the induction of clonal expansions, their spatio-temporal growth characteristics, and the first-passage-time distributions of malignant transformations. Consistency of the resulting multistage model with population level data will be tested by fitting the model to the incidence of esophageal adenocarcinoma in the SEER registry. Public health relevance: This project seeks to improve our understanding of how tissue architecture, in particular the crypt structure of intestinal epithelia, modulates the accumulation of genetic lesions, clonal sxpansion and evolution in neoplasms. Synthesizing the various aspects of this problem into a more nformed theory of multistage carcinogenesis will require an interdisciplinary approach. Although the biological questions and mathematical models that address them are primarily formulated in the context of the pre-malignant condition Barrett's esophagus, which is one of the few human conditions in which neoplastic progression can be directly observed over time, this research has wider implications for understanding the role of tissue architecture in carcinogenesis. This includes consequences for cancer screening, early detection, and the testing of specific intervention and prevention strategies. ? ?
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