Coupled Biological and Mathematical Model of Neuronal P

描述（由申请人提供）：生物学中的一个基本问题是如何精心组织哺乳动物大脑的发展是精心安排的。目前的知识表明，大脑发育过程中的模式形成是由多种信号引导的，包括可扩散的神经营养因子和包括粘附分子在内的细胞外基质蛋白的预形成分布。这些元素的相对贡献和每种类型信号的排列数量是未知的。为了更好地了解神经干细胞（NSCs）在体内的运动和分化，我们建议建立一个数学模型，使用细胞培养系统为模型提供定量数据。我们将检验一个假设，即NSC群体中的单个细胞通过迁移和分化来响应环境的能力是不同的。作为这一假设的推论，我们将测试NSCs是否以不同的行为响应来自扩散神经营养因子和细胞外基质（ECM）蛋白预形成分布的独特信号组合。基于这一假设，我们提出以下具体目标：1)建立细胞外基质蛋白和扩散因子在NSC模式中的作用的生物学模型。2)建立一个数学模型，可以预测生物模型中扰动的结果；3)使用器官培养系统对数学模型进行NSC模式测试。目前的团队已经做好了实施该项目的充分准备，包括一名发育生物学家、一名分子生物学家、一名聚合物化学家、一名数学家和一名数值建模师。该组中的几个人已经合作多年，在提交申请之前，该组在一年的时间里会面并讨论了这个问题。这种跨学科的方法将为组织整合过程中干细胞行为的过程提供基本的见解。

DESCRIPTION (provided by applicant): A fundamental question in biology is how development of the elaborately organized mammalian brain is orchestrated. Current knowledge suggests that the pattern formation during brain development is guided by a variety of signals including diffusible neurotrophic factors and preformed distributions of extracellular matrix proteins including adhesion molecules. The relative contributions of these elements and the number of permutations of each type of signal is unknown. To develop a better understanding of the movement and differentiation of neural stem cells (NSCs) in vivo, we propose to develop a mathematical model, using a cell culture system to provide quantitative data for the model. We will test the hypothesis that individual cells in a NSC population are diverse in their capability of responding to their environment by migration and differentiation. As a corollary to this hypothesis, we will test whether NSCs respond with different behaviors to unique combinations of signals from diffusible neurotrophic factors and preformed distributions of extracellular matrix (ECM) proteins. Based on this hypothesis, we propose the following specific aims: 1) Develop a biological model to test the role of extracellular matrix proteins and diffusible factors on NSC patterning. 2) Develop a mathematical model that can predict the outcome of perturbations in the biological model, and 3) Test the mathematical model using an organ culture system for NSC patterning. The current team is well prepared to carry out the proposed project and includes a developmental biologist, a molecular biologist, a polymer chemist, a mathematician, and a numerical modeler. Several individuals in this group have collaborated for many years and the group met and discussed this problem over the period of a year before submitting the application. This interdisciplinary approach will provide fundamental insights into the process of stem cell behavior during tissue integration.