Rule-based modeling approaches, which are based on the principles of chemical kinetics and diffusion and enabled by an expanding armamentarium of sophisticated software tools (e.g., BioNetGen/NFsim), offer spe- cial advantages for studying the dynamics of interactions among multisite signaling proteins. Rule-based mod- els can capture the effects of polymerization-like reactions and multisite post-translational modifications over time scales of seconds to hours while incorporating constraints imposed by molecular structures. Furthermore, with a rule-based approach to model formulation, it is possible to construct and analyze larger, more compre- hensive models for cellular regulatory systems than with traditional modeling approaches because of the op- portunity to represent systems concisely and at a high level of abstraction using formal rules for biomolecular interactions. Rules can often be processed to automatically derive traditional model forms, such as a coupled system of ordinary differential equations (ODEs). However, when the system state space implied by rules is exceedingly large, the use of simulation engines based on network-free algorithms becomes necessary and model analysis is limited by the high computational cost of the stochastic simulations. In addition, in these cir- cumstances and others, parameter identification and uncertainty quantification (UQ) are extremely challenging. We will address these problems by improving the efficiency of simulation, fitting, and UQ tools and by leverag- ing distributed computing resources. Recently, we developed novel algorithms for accelerating stochastic simu- lations, a toolbox of parallelized metaheuristic optimization methods for fitting, and implementations of Markov chain Monte Carlo (MCMC) methods for Bayesian UQ. This toolbox, called PyBioNetFit (PyBNF), leverages standardized formats for defining and sharing models (e.g., core SBML and BNGL) and is compatible with var- ious simulators. Here, we propose to develop general-purpose software implementations for accelerated net- work-free (stochastic) simulation and for restructuring rule-based models (i.e., optimizing rules so as to mini- mize the number of rule-implied equations). We will also provide a new interface to CVODE and CVODES for numerical integration of ODEs, forward sensitivity analysis, and adjoint sensitivity analysis. Furthermore, we will extend the biological property specification language (BPSL) of PyBNF to make this means for formalizing qualitative data more expressive. In addition, we will add gradient-based optimization and MCMC methods to PyBNF and built-in support for Smoldyn, a simulator for (rule-based) spatial stochastic models. These im- ?? provements will facilitate grounding of models in data. We will test and validate new tools by building models ?? for IgE receptor (Fc RI) signaling in collaboration with quantitative experimentalists. We will focus on models ?? for Fc RI-Lyn interaction within the context of a heterogeneous plasma membrane consisting of liquid ordered and disorded regions and Fc RI-mediated activation of Syk. These planned applications will ensure that our software development activities are directed at useful capabilities and will provide capability demonstrations.

Public Health Relevance

Cellular information processing is mediated by dynamic interactions among multisite signaling proteins. Rule- based models can help us obtain a predictive understanding of these interactions and their consequences and to manipulate cell signaling systems for therapeutic purposes. In this project, we will advance the development of software that enables rule-based modeling and apply new tools in collaboration with quantitative experimen- talists to advance understanding of IgE receptor signaling, which plays a central role in allergic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM111510-05
Application #
9970892
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Resat, Haluk
Project Start
2014-08-01
Project End
2024-04-30
Budget Start
2020-06-01
Budget End
2021-04-30
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Northern Arizona University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
806345542
City
Flagstaff
State
AZ
Country
United States
Zip Code
86011
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