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首页> 外文学位 >A Multiscale Modeling Study of the Mammary Gland: Using Mathematical Modeling and Computer Simulation to Study the Roles of Cell Phenotypic Dynamics and Molecular Signaling in the Pubertal End Bud and Postmenopausal DCIS Initiation.
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A Multiscale Modeling Study of the Mammary Gland: Using Mathematical Modeling and Computer Simulation to Study the Roles of Cell Phenotypic Dynamics and Molecular Signaling in the Pubertal End Bud and Postmenopausal DCIS Initiation.

机译：乳腺的多尺度建模研究：使用数学建模和计算机模拟研究细胞表型动力学和分子信号传导在青春期末芽和绝经后DCIS启动中的作用。

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摘要

Multiscale, hybrid computer modeling has emerged as a valuable tool in the fields of computational systems biology and mathematical oncology. In this work, we present an overview of the motivations for, and development and implementation of, three hybrid multiscale models of the mammary gland system and early stage ductal carcinoma in situ (DCIS) in the gland. Pubertal mammary gland development was described first using a two-dimensional, lattice-based hybrid agent-based model description of the mammary terminal end bud (TEB), and then with a three-dimensional lattice-free TEB model. Both models implement a discrete, agent-based description of the cell scale, and a continuum, finite element method description of tissue scale spatiotemporal molecular profiles, which are explicitly linked into a hybrid model. This lattice-free pubertal development TEB model was then transitioned into a post-menopausal early stage DCIS model, used for study of the phenotypic dynamics and molecular signaling disruptions involved in development of the DCIS tumor mass. Both TEB and DCIS models implemented simplified, literature-based cellular phenotypic developmental hierarchies and endocrine and paracrine signaling pathways. All models provided valuable insights into the effects of these aspects on the development of both the healthy gland and the pre-invasive DCIS cancer state, and results from model outputs were found to be within literature supported ranges. Cells of both healthy and cancerous phenotypes were found to be sensitive to changes in molecular signaling intensities and phenotypic hierarchies, which played an important part in overall development in both cases, with all cases demonstrating a greater effect of upstream estrogen paracrine signaling relative to the downstream AREG-FGF epithelial to stromal pathway also tested. Here, we provide detailed descriptions of these studies and results, as well as other useful discoveries, and also an overview of the modeling approaches, techniques, and rationale for their specific designs and implementations.
机译：多尺度混合计算机建模已成为计算系统生物学和数学肿瘤学领域中的一种有价值的工具。在这项工作中，我们概述了乳腺系统和腺体早期导管原位癌（DCIS）的三种混合多尺度模型的动机，开发和实施。首先使用乳腺末端芽（TEB）的二维基于格的基于混合剂的模型描述来描述青春期乳腺的发育，然后使用三维无格的TEB模型来描述。两种模型都实现了对细胞尺度的基于代理的离散描述，以及组织尺度时空分子分布的连续，有限元方法描述，它们明确地链接到混合模型中。然后将这种无晶格的青春期发育TEB模型转换为绝经后早期DCIS模型，用于研究DCIS肿瘤块发展中涉及的表型动力学和分子信号传导破坏。 TEB和DCIS模型都实现了简化的基于文献的细胞表型发育层次以及内分泌和旁分泌信号通路。所有模型都提供了关于这些方面对健康腺体和浸润前DCIS癌症状态发展的影响的宝贵见解，并且模型输出的结果被发现在文献支持的范围内。发现健康表型和癌表型的细胞均对分子信号强度和表型层次的变化敏感，这在这两种情况下均对总体发展起重要作用，所有情况均表明上游雌激素旁分泌信号相对于下游具有更大作用还测试了AREG-FGF上皮至基质的途径。在这里，我们提供了对这些研究和结果的详细描述，以及其他有用的发现，并对它们的具体设计和实现的建模方法，技术和原理进行了概述。

著录项

  • 作者

    Butner, Joseph D.;

  • 作者单位

    The University of New Mexico.;

  • 授予单位 The University of New Mexico.;
  • 学科 Biomedical engineering.
  • 学位 Ph.D.
  • 年度 2017
  • 页码 178 p.
  • 总页数 178
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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