Modeling Cell Regulatory Networks

描述（由申请人提供）：本项目的总体目标是开发细胞信号网络的详细空间模型，以了解信号组分微域的起源和动力学。我们将结合联合收割机的虚拟细胞程序中开发的空间逼真的模型与实验，以了解微畴的特性。拟议的项目是基于以下中心假设：“的动态空间定位以及活动的监管机构将有助于幅度和位置的信号网络内的信息流”。为了验证这一假设，我们建立了一个简单的网络，包括在神经元细胞中的cAMP和MAP-激酶1，2途径。使用这个网络，我们将确定的位置，浓度和活性状态的关键上游刺激成分的系统在空间上定义的域的激活MAP激酶1，2的发展中的作用。具体的问题包括不同水平的β-肾上腺素能受体占有对MAP-激酶活化程度的影响以及活性MAP-激酶的空间域;在β-肾上腺素能受体与腺苷酸环化酶5和2的偶联中，Gs的不同GT α活性速率的影响，以及活化的MAP-激酶1的空间结构域的随后特征，2和不同水平的激活蛋白激酶A的MAP-激酶活性的程度和空间定位的影响。我们还将定义信号网络的负调节因子的作用，例如磷酸二酯酶和蛋白磷酸酶在确定激活的MAP激酶1的空间结构域的特征中的作用，2我们将通过分析树突的长度和与细胞体的距离之间的关系以及树突的长宽比在确定细胞的空间结构中的作用，来研究细胞形态在确定空间结构中的作用。激活的MAP激酶的空间结构域。通过这样的分析，我们希望定义参与确定细胞内信号分子微区特征的关键标准。

DESCRIPTION (provided by applicant): The overall goal of this project is to develop detailed spatial models of cell signaling networks to understand the origins and dynamics of microdomains of signaling components. We will combine spatially realistic models developed in the program Virtual Cell with experiments to understand the characteristics of microdomains. The proposed project is based on the following central hypothesis: "the dynamics of spatial localization as well as activity of the regulators will contribute to amplitude and location of information flow within the signaling network". To test this hypothesis we have set up a simple network consisting of camp and MAP-kinase 1, 2 pathways in neuronal cells. Using this network we will determine the role of the location, concentrations and activity state of key upstream stimulatory components of the systems in the development of spatially defined domains of activated MAP-kinase 1,2. Specific questions include the effect of varying levels of beta-adrenergic receptor occupancy on the extent of MAP-kinase activation as well as the spatial domains of active MAP-kinase; the effect of varying GTPase activity rates of Gs in the coupling of beta-adrenergic receptor to adenylyl cyclases 5 and 2, and the consequent characteristics of the spatial domains of activated MAP-kinase 1,2 and the effect of varying levels of activation of protein kinase A on the extent and spatial localization of MAP-kinase activity. We will also define the role of negative regulators of the signaling network, such as phosphodiesterases and protein phosphatases in determining the characteristics of the spatial domains of activated MAP-kinases 1,2 We will study the role of cellular morphology in defining spatial domains by analyzing the relationship between the length of dendrites and distance from the cell body as well as the length to breadth ratios of dendrites in determining the spatial domains of activated MAPkinase. From such analysis we hope to define the key criteria involved in determining the characteristics of microdomains of signaling molecules within the cell.