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Modeling Dynamics of Salivary Gland Branching Morphogenesis

唾液腺分支形态发生的动力学建模

基本信息

批准号：
8291130
负责人：
MELINDA LARSEN
金额：
$ 29.95万
依托单位：
STATE UNIVERSITY OF NEW YORK AT ALBANY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8291130
关键词：
Acinar Cell Actins Address Adverse effects Affect Basement membrane Biochemical Biological Models Cleaved cell Clinical Complex Computer Simulation Cytoskeleton Data Development Effectiveness Engineering Epithelial Experimental Models Generations Grant Growth Growth Factor Head and Neck Neoplasms Knowledge Lead Life Link Lung Mediating Methods Modeling Modification Molecular Biology Morphogenesis Myosin ATPase Patients Play Predictive Value Process Radiation therapy Research Rho-associated kinase Role Saliva Salivary Glands Signal Pathway Signal Transduction Software Tools Staging Structure Syndrome System Testing Tissue Engineering Tissues Training Translating Work base cell behavior cellular engineering experimental analysis improved inhibitor/antagonist insight mathematical model research study simulation three dimensional structure tool user-friendly

项目摘要

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(申请人提供)：本申请是一名实验生物学家和一名理论数学家之间的合作项目，目的是开发一个模拟框架来模拟唾液腺分支形态发生的早期阶段，并创建一个可用于在此背景下预测细胞行为的交互工具。现有的唾液腺工程策略一直无法创建复杂的分支结构或成功地产生分泌唾液的腺泡细胞，这可能与这些模型中缺乏合适的三维结构有关。尽管目前临床上需要人工唾液腺来替代患有干燥综合征或头颈部肿瘤放射治疗副作用的患者受损的唾液产生组织，但几乎没有预测工具可用于模拟细胞行为。为了设计分支组织，我们需要了解分支在发育过程中是如何发生的，以及信号通路如何转化为物理变化。虽然已经确定了许多在分支中起作用的信号通路和结构成分，但到目前为止，它们还没有被整合到一个解释分支形态发生的综合模型中。仅用传统的分子生物学方法很难理解这种高度动态的结构过程。只有实验和数学模型之间的密切联系才能使人们对分支形态发生过程有一个完整的、系统的理解。我们之前生成了一个模拟框架，用于模拟基于局部增殖的肺分支。这个模型是有限的，因为基底膜的动力学对分支是至关重要的。我们的假设是，Rho激酶(ROCK)介导的信号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。为了应对这一假说并建立一个框架来理解基底膜动力学在分支形态发生中的作用，我们提出了五个具体目标：特定目标1基于水平集方法建立唾液腺分支形态发生模拟框架，特定目标2开发实验模型系统并将实验结果与新的数学模型和模拟框架的预测进行比较，特定目标3研究细胞骨架抑制剂在分支形态发生中的作用并利用这些数据对模型进行训练，特定目标4确定岩石抑制剂是否影响分支形态发生过程中的细胞骨架张力，以及特定目标5确定岩石影响分支形态发生的细胞机制。作为该项目的结果而开发的强大的模拟框架和数学模型将是朝着开发唾液腺分支形态发生的综合模型迈出的关键的第一步。值得注意的是，它将通过揭示缺失的环节和为未来研究提供方向来指导实验者。此外，随着获得更多的数据，数学模型和模拟框架可以进行修改，这将为我们提供一种工具来预测并最终控制细胞在不同基质基质上的行为，从而实现唾液腺功能的智能工程。项目简介：从这笔赠款中获得的数据将促进关于基底膜在控制唾液腺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，将生化和物理控制的实验分析结合在一起。该模型将在适当的数值框架内实施。这个软件工具将可以通过前端用户友好的界面访问，这样其他实验生物学家就可以在用活组织进行实验之前，将其用作检验硅胶假说的研究工具。最后，在生成允许我们在此背景下描述和预测细胞行为的模型时，我们将深入了解用于组织工程的控制细胞的新方法，这些组织工程需要预测细胞行为。这项工作将导致组织工程新模型的产生。