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.

发育中的乳腺的结构受刺激性和抑制性上皮上皮和上皮细胞相互作用（例如，信号，粘附）调节。尽管乳腺发育生物学家收集了大量分子和细胞数据，但仍然存在基本问题。例如，尚不清楚各种类型的细胞如何组织成管道。组织如何受到系统扰动的影响，例如更改的信号传导过程？这些问题的答案依赖于对正常导管形态发生和维护的信号传导和行为“规则”的理解。对这些相互作用的实验研究，并由数学模型补充，可以帮助促进对这些规则的理解和定义。在该项目中，研究人员采用联合实验和数学建模方法来研究乳腺发育，重点是导管形态发生。关于细胞和组织水平参数，研究人员设计了特定的实验，以测量模型参数并验证模型结果。特别重点将放在信号传导与接收细胞类型的性质上。同时，互补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与细胞尺度模型之间的差距，并具有详细的细胞排列。这个综合项目将允许预测响应系统扰动（例如由于突变或表观遗传事件引起的功能丧失）而发生的情况。这可以提供有关异常发育计划的出现和肿瘤启动的见解。此处开发的方法将适用于用肺，唾液，嗅觉上皮和前列腺腺等分支结构的其他器官建模。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，包括开发其他组织和器官，伤口愈合和组织再生，其特征是在广泛的时空和时间尺度上共同发生的过程。 生物学的基本问题之一是组织和器官如何发展和组织。发育过程是在细胞内部和外部以及环境之间发生复杂的机械和信号传导过程的结果。仅使用基于常规的实验方法，这种复杂的过程很难理解。最近，人们已经认识到，数学建模可以通过产生实验测试的假设来为实验研究提供独特的补充工具，并且使用实验研究的综合实验和计算方法可能比使用实验研究更强大，从而识别导致非直觉发展行为的机制，从而在实验中经常观察到非直觉的发育行为。但是，发展过程涉及在各种空间和时间生物学量表之间进行的相互作用。因此，应开发，在不同水平的复杂性下描述生物学行为的新数学模型应开发，链接在一起并在实验上进行验证，以提供理论预测框架，以补充当前的发展生物学研究。这正是该项目将在乳腺的背景下解决的问题，为此，各种类型的细胞如何组织起来以及该组织如何受到对系统（例如突变）的扰动的影响。具体而言，这些问题将通过利用数学和计算建模研究人员的补充专业知识以及实验技术来解决，以创建和分析用于乳腺开发的多尺度建模框架。将测量模型中的参数，并使用专门设计的实验来验证模型。综合工作提出了进一步发展一个综合的多尺度计算框架的必要第一步，该框架能够准确预测正常和异常的乳腺形态的发展。