Core F & G: Systems/Modeling & Computation

PENTACON在确定NSAID特异性的分子水平原因方面面临的中心挑战 疗效与不良反应是对不同细胞活动的综合计算模型 非甾体抗炎药给药受到干扰的组件。正是在这两个核心中，整合了我们的 系统生物学和建模的方法。在系统、建模和计算核心中，我们 描述PENTACON将如何产生大于其组成部分总和的结果。我们会 使用基于网络的离散和动态计算模型对行为和功能进行集成建模 保护不同的生物分子，说明细胞谱系和环境影响在 基因组和环境变异。我们知道这个系统中的复杂程度，但我们可能不知道 直接做模特。事实上，一些元素甚至可能违反我们的假设，例如剪接变体 和表观基因组的离散影响。我们通过(1)多种形式的组合来应对这些挑战 方法，包括探索性研究(如微生物组数据)和(2)定向建模工作和 模拟和实验验证的紧密迭代，具有可翻译的定量函数输出 直接传给人类。我们还将采用灵活的方法，更新信息的建模方法 这是从我们的分析中得出的。

A central challenge for PENTACON in identifying molecular-level causes of NSAID-specificity with respect to efficacy vs. adverse effects is the integrative computational modeling of the activity of the diverse cellular components that are perturbed upon NSAID administration. It is in these two cores that integrate our approaches to systems biology and modeling. In the Systems, Modeling and Computation Cores we describe how PENTACON will produce an outcome that is greater than the sum its component parts. We will use network-based discrete and dynamic computational models to integratively model behavior and functional conservation of diverse biomolecules, accounting for cell-lineage and environmental effects in the context of genomic and environmental variation. We are aware of the levels of complexity in this system that we may not be directly modeling. Indeed, some elements may even violate our assumptions, for example splice variants and discrete impacts of the epigenome. We address these challenges through (1) a combination of diverse approaches, including exploratory studies (such as for microbiome data) and (2) directed modeling efforts and close iteration of modeling and experimental verification with quantitative functional outputs that translate directly to humans. We will also adopt a flexible approach, updating the modeling approaches to information that emerges from our analyses.