Hardening Software for Rule-based Modeling.

用于基于规则的建模的强化软件。

• 批准号: 8753042
• 负责人: William S Hlavacek
• 金额: $ 34.27万
• 依托单位: NORTHERN ARIZONA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8753042
• 关键词: Address; Algorithmic Software; Algorithms; Automobile Driving; Behavior; Binding; Biochemical; Biological; Cell model; Cereals; Code; Complex; Computer software; Computing Methodologies; Coupled; Data; Data Analyses; Data Set; Decision Making; Defect; Dependence; Diagnosis; Differential Equation; Ensure; Environment; Equation; Etiology; Event; Exhibits; Goals; Imagery; Kinetics; Methods; Modeling; Nonlinear Dynamics; Phosphorylation; Property; Proteomics; Qualifying; Reaction; Receptor Protein-Tyrosine Kinases; Research; Research Personnel; Research Project Grants; Signal Transduction; Simulate; Site; Software Engineering; Software Tools; Solutions; Specific qualifier value; Study models; System; Systems Biology; Testing; Time; Translating; Tyrosine; Tyrosine Phosphorylation; Uncertainty; Update; Writing; base; cluster computing; combinatorial; design; experience; improved; information processing; novel; open source; public health relevance; research study; simulation; software development; tool

DESCRIPTION (provided by applicant): Approximately 30 software tools have been developed for rule-based modeling of biomolecular interaction networks. These tools enable new types of modeling studies. They are particularly useful for investigating biomolecular site dynamics: changes in the states of the functional sites of biomolecules, such as site-specific phosphorylation dynamics. With few exceptions, available software for rule-based modeling is still in a primitive state and critical capabilities are simply unavailable. Existing tools do not provide capabilities that are routinely used in ODE modeling, such as fitting, sensitivity analysis and bifurcation analysis. Moreover, simulators that implement the most generally applicable simulation methods (direct methods) are not being actively developed, and these simulators need to be updated to properly handle certain classes of important problems as well as to offer greater efficiency. We propose to create a toolbox of software tools that will advance the field of computational systems biology. We have identified gaps in existing rule-based software capabilities and present a systematic approach to fill them. Our plan for developing more efficient direct simulation tools involves a two-pronged approach: enabling use of available simulators in distributed computing environments and developing new equation-free computational methods that offer the promise of greater efficiency and integration with existing data analysis software packages. In developing this toolbox, we will improve software for rule-based modeling; integrate existing software tools, and developing new tools for sensitivity and bifurcation analysis and data fitting. These tools are needed so that rule-based modelers can leverage data suited for calibrating parameters of rule-based models, including high-throughput proteomic data. These tools are also needed for diagnosing the dependence of predicted model behaviors on uncertain model parameters, designing experiments to reduce uncertainty in parameter estimates, and elucidating bifurcations (points in parameter space at which sharp transitions in behavior occur). We will test and validate these tools by building a model of receptor tyrosine kinase (RTK) signaling and using this model to investigate how site-specific tyrosine phosphorylation depends on properties of RTK tyrosines and their binding partners. This focus on a driving biological question will ensure that our software development activities are directed at useful capabilities. Our experience developing software tools for rule-based modeling, as well as novel methods, uniquely qualifies us to carry out this proposed project.

描述（申请人提供）：已经开发了大约30个软件工具，用于基于规则的生物分子交互网络的建模。这些工具可实现新型的建模研究。它们对于研究生物分子位点动力学特别有用：生物分子功能部位的状态的变化，例如特定于位点特异性的磷酸化动力学。除少数例外，可用的基于规则的建模的软件仍然处于原始状态，关键功能根本无法使用。现有工具不提供在ODE建模中常规使用的功能，例如拟合，灵敏度分析和分叉分析。此外，实施最普遍适用的模拟方法（直接方法）的模拟器并未积极开发，并且需要更新这些模拟器，以正确处理某些重要类别的重要问题以及提供更高的效率。我们建议创建一个软件工具工具箱，以推动 计算系统生物学。我们已经确定了现有的基于规则的软件功能的空白，并提出了一种填充它们的系统方法。我们开发更有效的直接仿真工具的计划涉及一种两管齐下的方法：启用在分布式计算环境中使用可用的模拟器，并开发新的无方程计算方法，这些方法提供了提高效率并与现有数据分析软件包集成的希望。在开发此工具箱时，我们将改善用于基于规则的建模的软件；整合现有的软件工具，并开发新的工具，以敏感性和分叉分析和数据拟合。需要这些工具，以便基于规则的建模者可以利用适合校准基于规则模型的参数的数据，包括高通量蛋白质组学数据。还需要这些工具来诊断预测模型行为对不确定模型参数的依赖性，设计实验以减少参数估计的不确定性，并阐明分叉（行为中急剧过渡的参数空间中的点点）。我们将通过构建一种受体酪氨酸激酶（RTK）信号传导模型来测试和验证这些工具，并使用该模型研究位点特异性酪氨酸磷酸化如何取决于RTK酪氨酸及其结合伙伴的性质。关注驾驶生物学问题的这种关注将确保我们的软件开发活动针对有用的功能。我们开发用于基于规则的建模的软件工具以及新颖的方法的经验使我们有资格执行此拟议项目。