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一个主要挑战是 有效性与副作用是不同细胞活性的综合计算模型， 这些成分在NSAID给药后受到干扰。正是在这两个核心中， 系统生物学和建模方法。在系统、建模和计算核心中， 描述PENTACON将如何产生一个大于其组成部分之和的结果。我们将 使用基于网络的离散和动态计算模型，对行为和功能进行综合建模 保护不同的生物分子，在环境中解释细胞谱系和环境效应， 基因组和环境变异。我们意识到这个系统的复杂程度， 直接做模特。事实上，有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。我们通过以下方式应对这些挑战：（1）结合各种 方法，包括探索性研究（如微生物组数据）和（2）定向建模工作， 通过量化功能输出进行建模和实验验证的紧密迭代， 直接用于人类。我们还将采用灵活的方法，更新信息建模方法 从我们的分析中浮现出来。

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.