Core F & G: Systems/Modeling & Computation

核心F

• 批准号: 8126760
• 负责人: Srinivas Ravi V Iyengar
• 金额: $ 31.14万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8126760
• 关键词: Accounting; Address; Adopted; Adverse effects; Adverse event; Animal Model; Behavior; Biological; Biological Models; Biological Process; Cell Lineage; Clinical; Communities; Complement; Computer Simulation; Confidentiality of Patient Information; Data; Data Analyses; Data Set; Databases; Development; Disease; Dose; Drug Formulations; Drug Kinetics; Drug effect disorder; Education; Eicosanoids; Elements; Event; Experimental Designs; Experimental Models; Funding; Genetic; Genomics; Homologous Gene; Human; Human Biology; Imagery; Individual; Intuition; Language; Link; Lipids; Machine Learning; Maps; Methods; Modeling; Molecular; Mus; Network-based; Non-Steroidal Anti-Inflammatory Agents; Organ; Organism; Outcome; Output; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Population; Process; Proteins; Quality Control; RNA Splicing; Regimen; Risk; Scientist; Signal Transduction; Specific qualifier value; Specificity; Sum; System; Systems Biology; Testing; Therapeutic Effect; Tissues; Translating; Treatment Efficacy; Update; Variant; base; computerized data processing; dosage; flexibility; insight; microbiome; network models; pharmacokinetic model; research study; response; simulation; small molecule

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.

PENTACON 面临的一个核心挑战是确定 NSAID 特异性的分子水平原因 功效与不良反应是不同细胞活性的综合计算模型 NSAID 给药后受到干扰的成分。正是在这两个核心中整合了我们的 系统生物学和建模方法。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 保护多种生物分子，考虑细胞谱系和环境影响 基因组和环境变异。我们知道这个系统的复杂程度，但我们可能不知道 直接建模。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 (1) 结合不同的方法来应对这些挑战 方法，包括探索性研究（例如微生物组数据）和（2）定向建模工作和 建模和实验验证的紧密迭代以及可转化的定量功能输出 直接针对人类。我们还将采取灵活的方法，更新信息的建模方法 这是我们的分析得出的结果。