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（由申请人提供）：开发模拟信号动态的数学工具极其重要。根据我们之前的实验数据和模拟结果，我们确信，为了准确、适当地模拟信号网络，我们不能忽视细胞膜（最终还有细胞质）的空间组织。我们在开发细胞膜的空间真实模拟并研究信号传导的启动方面拥有丰富的经验。然而，虽然这些模拟的计算量非常大，但细胞信号传导的关键方面只能在整个细胞膜或至少是其重要部分的背景下才能正确表示。相对于其他常用的受体系统（即 EGFR、VEGFR），Th Fc¿RI 系统提出了额外的挑战，因为 Fc¿RI/IgE 复合物本质上表现为二价受体，而抗原通常是多价的（价从 3 到 24）。因此，通过抗原对 FceRI/IgE 复合物的多价交联，可能会出现任意大的聚集体。由于可能的聚合类型数量的组合爆炸，该问题非常适合基于规则的生物分子网络建模方法。因此，FceRI/IgE 系统的本质需要将基于规则的方法与空间建模框架相集成。我们将开发一种粗粒度的方法来整合详细（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）将详细的微观模拟和实验数据集成到捕获细胞膜重要部分的介观模型中，以及（b）提供一种机制，将大分子聚集体的空间流动性和空间约束包含在Fc epsilon RI系统的基于规则的随机模型中。