A Spatially coarse-grained, rule-based frame work for modeling large molecular

用于建模大分子的空间粗粒度、基于规则的框架

• 批准号: 8503615
• 负责人: Jeremy S Edwards
• 金额: $ 32.54万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-05 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8503615
• 关键词: Address; Antigens; Cell membrane; Cells; Cereals; Complex; Cytosol; Data; Development; Epidermal Growth Factor Receptor; Explosion; Fc epsilon RI; IgE; Methodology; Microscopic; Modeling; Molecular; Nature; Relative (related person); Signal Transduction; Simulate; System; Vascular Endothelial Growth Factor Receptor; Work; base; combinatorial; crosslink; experience; network models; receptor; simulation; spatial neglect; tool

DESCRIPTION (provided by applicant): The development of mathematical tools to simulate signaling dynamics is extremely important. Based on our previous experimental data and simulation results, we are convinced that to accurately and appropriately model signaling networks, we cannot neglect the spatial organization of the cell membrane (and ultimately the cytosol as well). We have extensive experience in developing spatially realistic simulations of the cell membrane and studied the initiation of signaling. However, while these simulations are extremely computationally intense, crucial aspects of cell signaling can only be correctly represented in the context of the entire cell membrane, or at least a significant portion of it. Th Fc¿RI system presents an additional challenge relative to other commonly studied receptor systems (i.e. EGFR, VEGFR), in that the Fc¿RI/IgE complex essentially behaves as a bivalent receptor, while the antigens are typically multivalent (valency from 3 to ¿24). As a result, arbitrarily large aggregates may emerge through the multivalent cross-linking of FceRI/IgE complexes by the antigen. Due to the combinatorial explosion of the number of possible aggregate types, this problem is eminently suited for the rule-based approach to bio-molecular network modeling. Thus, the nature of the FceRI/IgE system requires the integration of the rule-based approach with a spatial modeling framework. We will develop a coarse grained methodology for integration of detailed (microscopic) and cell-level (mesoscopic) simulations and experimental results. This framework will help address both challenges described above, namely (a) integrate detailed, microscopic simulations and experimental data into a mesoscopic model that captures a significant portion of the cell membrane and (b) provide a mechanism to include spatial mobility and steric constraints for large molecular aggregates in a rule-based, stochastic model of the Fc epsilon RI system.

描述（由适用提供）：开发模拟信号动态的数学工具非常重要。基于我们以前的实验数据和仿真结果，我们确信要准确，适当地对信号网络进行建模，我们不能忽略细胞膜的空间组织（最终也是细胞质）。我们在开发细胞膜的空间逼真的模拟方面拥有丰富的经验，并研究了信号传导的启动。但是，尽管这些模拟在计算上非常强烈，但细胞信号的关键方面只能在整个细胞膜的背景下正确表示，或者至少在其中很大一部分。相对于其他常用的受体系统（即eGFR，VEGFR），FC¿RI系统提出了额外的挑战，因为Fc？ri/IgE复合物本质上是双重接收器的表现，而抗原通常是多价（价为3至3至€24的价值）。结果，任意较大的聚集体可以通过抗原的FcERI/IgE配合物的多价交联出现。由于可能的骨料类型数量的组合爆炸，因此此问题非常适合基于规则的生物分子网络建模的方法。这就是FCERI/IGE系统的性质要求将基于规则的方法与空间建模框架集成。我们将开发一种粗糙的方法，用于整合详细的（微观）和细胞级（介观）模拟和实验结果。该框架将有助于解决上述两个挑战，即（a）集成的详细，微观模拟和实验数据纳入介观模型，该模型捕获了细胞膜的很大一部分，并且（b）提供了一种机制，提供了一种机制，可以包括空间迁移率和基于基于规则的，基于规则的，fc eps ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri ri conteric的限制。