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

描述（由申请人提供）：开发数学工具来模拟信号动态是极其重要的。基于我们之前的实验数据和模拟结果，我们相信，要准确和适当地建模信号网络，我们不能忽视细胞膜的空间组织（最终也包括胞质溶胶）。我们在开发细胞膜的空间逼真模拟方面拥有丰富的经验，并研究了信号的启动。然而，虽然这些模拟是非常密集的计算，细胞信号的关键方面只能在整个细胞膜的情况下正确表示，或至少在它的重要部分。Th Fc <$RI系统相对于其他通常研究的受体系统提出了额外的挑战（即EGFR、VEGFR），因为Fc RI/IgE复合物基本上表现为二价受体，而抗原通常是多价的（3至24价）。因此，通过抗原对FceRI/IgE复合物的多价交联，可以出现任意大的聚集体。由于组合爆炸的数量可能的聚合类型，这个问题是非常适合基于规则的方法来生物分子网络建模。因此，FceRI/IgE系统的性质需要将基于规则的方法与空间建模框架整合。我们将开发一种粗粒度的方法，用于集成详细（微观）和细胞级（介观）的模拟和实验结果。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整合到捕获细胞膜的重要部分的介观模型中，以及（B）提供一种机制，以在Fc β RI系统的基于规则的随机模型中包括大分子聚集体的空间移动性和空间约束。

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.