Modeling Dynamics of Salivery Gland Branching Morphogenesis

唾液腺分支形态发生的动力学建模

• 批准号: 7529980
• 负责人: Dirk Hartmann
• 金额: $ 31.98万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT ALBANY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7529980
• 关键词: Acinar Cell; Actins; Address; Adverse effects; Affect; Area; Basement membrane; Biochemical; Biological; Biological Models; Biological Sciences; Cell Proliferation; Cell model; Cell-Cell Adhesion; Cell-Matrix Junction; Cells; Characteristics; Cleaved cell; Clinical; Collaborations; Complex; Computer Simulation; Condition; Consultations; Coupling; Cultured Cells; Cytoskeleton; Data; Derivation procedure; Development; Effectiveness; Embryo; Engineering; Environment; Epithelial; Evolution; Experimental Models; Fibroblast Growth Factor; Fibronectins; Flowcharts; Future; Generations; Gland; Goals; Grant; Growth; Growth Factor; Head and Neck Cancer; Head and Neck Neoplasms; Image; Image Analysis; In Vitro; Individual; Institution; Knowledge; Laboratories; Lead; Life; Link; Localized; Lung; Mechanics; Mediating; Membrane; Methods; Microscope; Microscopic; Modeling; Modification; Molecular; Molecular Biology; Morphogenesis; Mus; Myosin ATPase; New York; Organ; Organ Culture Techniques; Organism; Pathway interactions; Patients; Phosphotransferases; Play; Predictive Value; Process; Radiation therapy; Research; Rho-associated kinase; Role; Saliva; Salivary Glands; Scientist; Signal Pathway; Signal Transduction; Sjogren' s Syndrome; Software Tools; Staging; Structure; Surface; Syndrome; System; Systems Analysis; Testing; Time; Tissue Engineering; Tissues; Training; Translating; Universities; Work; base; cell behavior; cellular engineering; cellular imaging; computer framework; computerized tools; desire; experience; experimental analysis; improved; in vivo; inhibitor/antagonist; insight; mathematical model; models and simulation; multi-scale modeling; novel; novel strategies; radiation effect; research study; scaffold; scientific computing; simulation; three dimensional structure; tool; user-friendly

DESCRIPTION (provided by applicant): This application is a collaborative project between an experimental biologist and a theoretical mathematician in order to develop a simulation framework to model the early stages of salivary gland branching morphogenesis and create an interactive tool that can be used to predict cell behavior within this context. Existing strategies for engineering salivary glands have been unable to create a complex branched structure or successfully produce saliva-secreting acinar cells, which may relate to the lack of appropriate 3D structure in these models. Although there is currently a clinical need for artificial salivary glands to replace the damaged saliva-producing tissue in patients suffering from Sj"gren's Syndrome or from side effects of radiation therapy for head and neck tumors, few predictive tools are available to model cell behavior. To engineer branched tissues, we need to understand how the branching occurs during development and how signaling pathways translate into physical changes. While many signaling pathways and structural components have been identified that play a role in branching, they so far have not been incorporated into a comprehensive integrated model that explains branching morphogenesis. This highly dynamic structural process can hardly be understood using conventional molecular biology methods alone. Only a close association between experiments and mathematical modeling will allow an integrated, systems level understanding of the process of branching morphogenesis. We previously generated a simulation framework to model lung branching based on localized proliferation. This model is limited since basement membrane dynamics are critical for branching. Our hypothesis is that basement membrane dynamics controlled by Rho kinase (ROCK)-mediated signaling is a critical component of salivary gland branching morphogenesis. To address this hypothesis and to create a framework for understanding the role of basement membrane dynamics during branching morphogenesis, we propose five specific aims: Specific Aim 1 Develop a simulation framework for salivary gland branching morphogenesis based on Level Set Methods, Specific Aim 2 Develop the experimental model system and compare experimental results with predictions of the new mathematical model and simulation framework, Specific Aim 3 Investigate the function of cytoskeletal inhibitors on branching morphogenesis and use this data to train the model, Specific Aim 4 Determine if ROCK inhibitors affect cytoskeletal tension during branching morphogenesis, and Specific Aim 5 Identify the cellular mechanism by which ROCK affects branching morphogenesis. The robust simulation framework and the mathematical models developed as a result of this project will constitute the first crucial step towards development of a comprehensive model of salivary gland branching morphogenesis. Significantly, it will guide experimentalists by revealing missing links and suggesting directions for future research. Further, the mathematical model and simulation framework can be modified as more data is obtained and will provide us with a tool to predict, and eventually, control cell behavior on different matrix substrates for intelligent engineering of a functional salivary gland. Project Narrative: The data obtained from this grant will advance basic scientific knowledge regarding the role of the basement membrane in control of branching morphogenesis in the salivary gland. In addition, we will create a mathematical model that incorporates experimental analysis of both biochemical and physical control. The model will be implemented in an appropriate numerical framework. This software tool will be accessible by a front end user-friendly interface, such that it will be available for other experimental biologists to use as a research tool for testing hypothesis in silico before experimenting with live tissue. Finally, in generating this model that allows us to describe and predict cell behavior within this context, we will gain insights into new methods for controlling cells for engineering of tissues which require prediction of cell behavior. This work will lead to generation of new models for tissue engineering.

描述（由申请人提供）：此应用程序是实验生物学家和理论数学家之间的协作项目，以开发一个模拟框架，以建模唾液腺分支分支形态发生的早期阶段，并创建一种交互式工具，该工具可用于在这种情况下用于预测细胞行为。现有的工程唾液腺策略无法创建复杂的分支结构或成功产生分泌唾液的腺泡细胞，这可能与这些模型中缺乏适当的3D结构有关。尽管目前有临床需要进行人造唾液腺来代替患有SJ“ Gren综合征或从放射治疗的副作用中，对于头颈部肿瘤的副作用而受损的唾液产生组织受损，但几乎没有预测性工具可用于模拟细胞行为。模拟细胞的行为。在工程上构造了构造的构造，我们需要在构造的过程中进行构建和构造的构造。确定在分支中起作用，迄今为止，它们尚未纳入分支形态发生的全面综合模型。该模型受到限制，因为地下室膜动力学对于分支至关重要。我们的假设是，由Rho激酶（岩石）介导的信号传导控制的基底膜动力学是唾液腺分支形态发生的关键组成部分。要解决这一假设并创建一个框架，以理解地下膜动力学在分支形态发生过程中的作用，我们提出了五个特定目的：特定目标1基于水平设置方法，开发了唾液腺分支形态发生的模拟框架，特定的目标2开发了实验模型系统，并在新的数学模型框架上进行了cy框架，并在cy框架上进行了比较，该目标是cy框架，cy框架的范围3，该框架的功能，功能3.分支形态发生并使用此数据来训练模型，具体目标4确定岩石抑制剂在分支形态发生过程中是否影响细胞骨架张力，而具体目标5确定了岩石影响分支形态发生的细胞机制。由于该项目而开发的强大仿真框架和数学模型将构成开发唾液腺分支形态发生的综合模型的第一步。值得注意的是，它将通过揭示缺失的链接并建议未来研究的方向来指导实验者。此外，随着获得更多数据，可以修改数学模型和仿真框架，并将为我们提供一种预测工具，并最终在不同矩阵基板上控制功能性唾液腺的智能工程上的细胞行为。项目叙述：从这笔赠款中获得的数据将促进有关基础膜在控制唾液腺中分支形态发生中的作用的基本科学知识。此外，我们将创建一个数学模型，结合生化和物理控制的实验分析。该模型将在适当的数值框架中实现。前端最终用户友好的界面将可以访问该软件工具，以便其他实验生物学家可以将其用作研究工具，以在实验实时组织之前测试硅的假设。最后，在生成该模型的过程中，我们可以在这种情况下描述和预测细胞行为，我们将深入了解用于控制需要预测细胞行为的组织的细胞的新方法。这项工作将导致组织工程的新模型。