Modeling Cell Regulatory Networks

细胞调控网络建模

• 批准号: 7905249
• 负责人: Srinivas Ravi V Iyengar
• 金额: $ 10.77万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7905249
• 关键词: Adenylate Cyclase; Adrenergic Receptor; Caliber; Camping; Cell Line; Cell model; Cell physiology; Cells; Cellular Morphology; Characteristics; Complex; Computer Simulation; Coupled; Coupling; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Dendrites; Development; Equation; Goals; Guanosine Triphosphate Phosphohydrolases; Kinetics; Length; Ligands; Location; MAPK1 gene; Mitogen Activated Protein Kinase 1; Mitogen-Activated Protein Kinases; Modeling; Movement; Neurons; Pathway interactions; Phosphoric Monoester Hydrolases; Property; Protein Isoforms; Protein Phosphatase 2A Regulatory Subunit PR53; Protein phosphatase; Proteins; Reaction; Regulation; Resolution; Role; Scheme; Signal Pathway; Signal Transduction; Signaling Molecule; Solutions; System; Testing; base; beta-adrenergic receptor; information processing; neuronal cell body; phosphodiesterase 4D; phosphoric diester hydrolase; programs; protein protein interaction; research study; virtual

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.

描述（由申请人提供）：该项目的总体目标是开发细胞信号网络的详细空间模型，以了解信号成分微域的起源和动态。我们将把 Virtual Cell 程序中开发的空间真实模型与实验相结合，以了解微域的特征。拟议的项目基于以下中心假设：“空间定位的动态以及调节器的活动将有助于信号网络内信息流的幅度和位置”。为了检验这一假设，我们在神经元细胞中建立了一个由 Camp 和 MAP 激酶 1、2 通路组成的简单网络。使用该网络，我们将确定系统关键上游刺激成分的位置、浓度和活动状态在激活的 MAP-激酶 1,2 空间定义域的发育中的作用。具体问题包括不同水平的 β-肾上腺素受体占据对 MAP 激酶激活程度以及活性 MAP 激酶的空间域的影响； β-肾上腺素能受体与腺苷酸环化酶 5 和 2 偶联时 Gs 的不同 GTP 酶活性速率的影响，以及激活的 MAP-激酶 1,2 空间域的后续特征，以及不同水平的蛋白激酶 A 激活对 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（例如磷酸二酯酶和蛋白磷酸酶）在确定激活的 MAP 激酶的空间域特征中的作用 1,2 我们将通过分析树突长度与距细胞体的距离之间的关系以及树突的长宽比在确定空间域特征中研究细胞形态在定义空间域中的作用。 激活的 MAPkinase 结构域。通过这样的分析，我们希望定义涉及确定细胞内信号分子微域特征的关键标准。