Collaborative Research: Multiscale Modeling of Mammary Gland Development

合作研究：乳腺发育的多尺度建模

• 批准号: 1562068
• 负责人: Vittorio Cristini
• 金额: $ 22万
• 依托单位: The University of Texas Health Science Center at Houston
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1562068&HistoricalAwards=false
• 关键词: Collaborative; Research; Multiscale; Modeling; Mammary

The structure of the developing mammary gland is regulated by stimulatory and inhibitory epithelial-epithelial and epithelial-stromal cell interactions (e.g., signaling, adhesion). While mammary developmental biologists have gathered a wealth of molecular and cellular data, fundamental questions remain. For example, it is still unknown how cells of various types become organized into a duct. How is the organization affected by system perturbations such as altered signaling processes? The answers to these questions rely on an understanding of signaling and behavioral "rules" governing normal ductal morphogenesis and maintenance. Experimental investigations of these interactions, complemented by mathematical models, can help facilitate the understanding and definition of these rules. In this project, the investigators employ a joint experimental and mathematical modeling approach to study mammary gland development with a focus on ductal morphogenesis. With respect to cellular and tissue level parameters, the investigators design specific experiments to measure model parameters and validate model results. Particular emphasis will be placed on the nature of the signaling vs. receiving cell type(s). In parallel, the complementary expertise will be leveraged and used to develop a multiscale mathematical and computational framework to bridge the gap between tissue scale models of ductal morphogenesis and cellular scale models with detailed cell arrangements. This integrative project will allow for predicting what occurs in response to system perturbations such as loss-of-function due to mutations or epigenetic events. This can provide insight on the emergence of abnormal development programs and the initiation of tumors. The methods developed here will be applicable to modeling other organs with branching architectures such as lung, salivary, olfactory epithelium and prostate glands. Beyond these applications, the new tools developed here will also impact other problems in the biological sciences including development of other tissues and organs, wound healing, and tissue regeneration that are characterized by processes occurring in concert over a wide range of space and time scales. One of the fundamental questions in biology is how tissues and organs develop and become organized. Developmental processes are the result of complex mechanical and signaling processes occurring inside and outside cells, and between cells and the environment. Such complex processes are very difficult to understand by using conventional experiment-based approaches alone. Recently, it has been recognized that mathematical modeling can provide a unique and complementary tool to experimental investigations by generating experimentally testable hypotheses, and that an integrated experimental and computational approach can potentially be more powerful than solely using experimental investigation, in identifying mechanisms responsible for non-intuitive developmental behavior frequently observed in experiments. However, the developmental processes involve interactions across a wide range of spatial and temporal biological scales. Thus, new mathematical models describing biological behavior at different scales, and at different levels of complexity, should be developed, linked together, and experimentally validated to provide a theoretical predictive framework to complement current developmental biology research. This is precisely what this project will address in the context of the mammary gland, for which it is still unknown how the cells of various types become organized and how this organization is affected by perturbations to the system such as from mutations. Specifically, these questions will be addressed by drawing on the complementary expertise of the researchers in mathematical and computational modeling and in experimental techniques to create and analyze a multiscale modeling framework for mammary gland development. The parameters in the models will be measured, and the models will be validated, using specifically designed experiments. The integrative work presents a necessary first step towards further development of a comprehensive, multiscale computational framework capable of accurately predicting the development of normal and abnormal mammary gland morphologies.

发育中的乳腺结构受刺激和抑制上皮细胞-上皮细胞和上皮细胞-基质细胞相互作用（如信号传导、粘附）的调节。虽然乳腺发育生物学家已经收集了大量的分子和细胞数据，但基本问题仍然存在。例如，我们仍然不知道不同类型的细胞是如何组织成导管的。系统扰动（如信号传递过程的改变）对组织有何影响？这些问题的答案依赖于对控制正常导管形态发生和维持的信号和行为“规则”的理解。这些相互作用的实验研究，辅以数学模型，可以帮助促进这些规则的理解和定义。在这个项目中，研究者采用联合实验和数学建模的方法来研究乳腺的发育，重点是导管的形态发生。对于细胞和组织水平的参数，研究人员设计了特定的实验来测量模型参数并验证模型结果。将特别强调信号与接收细胞类型的性质。与此同时，互补的专业知识将被利用并用于开发多尺度数学和计算框架，以弥合导管形态发生的组织尺度模型和具有详细细胞排列的细胞尺度模型之间的差距。这个综合项目将允许预测系统扰动的反应，如由于突变或表观遗传事件导致的功能丧失。这可以为异常发育程序的出现和肿瘤的发生提供见解。该方法将适用于其他具有分支结构的器官的建模，如肺、唾液、嗅上皮和前列腺。除了这些应用之外，这里开发的新工具还将影响生物科学中的其他问题，包括其他组织和器官的发展，伤口愈合和组织再生，这些问题以在广泛的空间和时间尺度上协同发生的过程为特征。生物学的一个基本问题是组织和器官是如何发育和组织起来的。发育过程是发生在细胞内外以及细胞与环境之间的复杂机械和信号过程的结果。这种复杂的过程是很难通过传统的基于实验的方法来理解的。最近，人们已经认识到，数学建模可以通过生成实验可测试的假设，为实验研究提供独特的补充工具，并且在确定实验中经常观察到的非直觉发育行为的机制方面，综合实验和计算方法可能比单独使用实验研究更强大。然而，发育过程涉及广泛的空间和时间生物尺度的相互作用。因此，应该开发新的数学模型来描述不同尺度和不同复杂程度的生物行为，将它们联系在一起，并通过实验验证，以提供一个理论预测框架，以补充当前的发育生物学研究。这正是这个项目将在乳腺的背景下解决的问题，对于乳腺，我们仍然不知道各种类型的细胞是如何组织起来的，以及这种组织是如何受到突变等系统扰动的影响的。具体来说，这些问题将通过利用研究人员在数学和计算建模以及实验技术方面的互补专业知识来解决，以创建和分析乳腺发育的多尺度建模框架。模型中的参数将被测量，模型将被验证，使用专门设计的实验。这项综合工作为进一步发展一个全面的、多尺度的计算框架提供了必要的第一步，该框架能够准确地预测正常和异常乳腺形态的发展。