MSM Scales of carcinogenesis: cells, crypts and cancer

描述(由申请人提供)： 该项目的主要目标是开发一个从细胞水平到人类人口水平的跨越时空尺度的致癌计算多尺度模型。具体地说，它包括多尺度和多阶段致癌模拟模型的模块化开发，该模型由三个主要组成部分组成：从细胞到增殖单元模块。检查点延迟、修复过程和干细胞的凋亡敏感性被认为是最佳的，以延缓肿瘤进展的过程。这一“最优化”问题将通过对增殖单位(隐窝)中干细胞种群动态平衡的确定性和随机性描述来解决。从增殖单元到组织模块。破坏组织结构并允许肿瘤克隆扩张的机制可能会产生不同的遗传损伤空间分布。这里开发的多尺度模型将用于探索隐窝分叉、上皮重建和细胞迁移在伤口愈合或不愈合的情况下产生的克隆的空间和遗传模式。从一个纸巾到一个人口模块。在组织水平上的微观模拟模型将被用来推导克隆扩张诱导的首次通过时间、其时空生长特征以及恶性转化的首次通过时间分布。所得到的多阶段模型与人口水平数据的一致性将通过将该模型与SEER登记中的食管腺癌发病率相匹配来进行测试。公共卫生相关性：这个项目试图提高我们对组织结构，特别是肠道上皮的隐窝结构，如何调控肿瘤中遗传损伤的积累、克隆扩散和进化的理解。将这个问题的各个方面综合成一个更具形式化的多阶段致癌理论将需要一种跨学科的方法。虽然解决这些问题的生物学问题和数学模型主要是在巴雷特食道癌前状态的背景下制定的，巴雷特食道是少数几种可以随着时间的推移直接观察到肿瘤进展的人类条件之一，但这项研究对理解组织结构在癌症发生中的作用具有更广泛的意义。这包括癌症筛查、早期发现以及特定干预和预防策略测试的后果。

DESCRIPTION (provided by applicant): 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.