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Multiscale Modeling of the Mammalian Circadian Clock: The Role of GABA Signaling

Multiscale Modeling of the Mammalian Circadian Clock: The Role of GABA Signaling. Michael A. Henson, UMass Amherst Erik D. Herzog, Washington U. Yannis Kevrekidis, Princeton Start Date: September 15, 2016. Model Context of Use. Intended Utility

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Multiscale Modeling of the Mammalian Circadian Clock: The Role of GABA Signaling

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  1. Multiscale Modeling of the Mammalian Circadian Clock: The Role of GABA Signaling Michael A. Henson, UMass Amherst Erik D. Herzog, Washington U. Yannis Kevrekidis, Princeton Start Date: September 15, 2016

  2. Model Context of Use • Intended Utility • Prediction of circadian clock connectivity, synchronization and entrainment properties • Connect core clock genes and ion channels at the individual cell level and network synchronization and entrainment behavior at the tissue level • Illustrate general computational techniques for model reduction and efficient simulation of heterogeneous cellular networks • Intended Audience • Circadian biologists • Computational system biologists • Complex network scientists • Computational scientists

  3. Model Credibility Plan: Key Components • Modular architecture: single neuron model, cell-to-cell coupling, multicellular model, network reduction and network simulation • MATLAB for initial module development followed by conversion into systems biology markup language (SBML) • Identification of one third-party evaluator: Dr. Stephanie Taylor (Colby College Computer Science Department) • Modeling tool assessment metrics include synchronization rates, entrainment dynamics and effects of pharmacological agents • Simulation tool assessment metrics include flexibility, speed and integration with modeling codes

  4. Model Credibility Plan: Timeline and Milestones • Year 1: The single neuron model and network generation method will be evaluated. • Year 2: The MATLAB codes developed in Year 1 will be converted to SBML and evaluated. The multicellular model and network reduction method will be evaluated. • Year 3: The MATLAB codes developed in Year 2 will be converted to SBML and evaluated. The drug administration model and network simulation method will be evaluated. MATLAB algorithms will be ported to high performance clusters and translated to FORTRAN or C++. • Year 4: The MATLAB codes developed in Year 3 will be converted to SBML and be provided. MATLAB and SBML codes for the drug simulation and optimization methods will be provided.

  5. Model Credibility Plan: Year 1 Progress • Project started only 6 months ago • Circadian system modeling • An improved single neuron model is under development • The third-party evaluator Dr. Taylor will evaluate the MATLAB model late this summer • Another third-party evaluator will be identified • Neural network simulation • Reduced-order network simulation methods have been developed • The third-party evaluator Dr. Taylor will evaluate the Fortran code early this summer • Another third-party evaluator will be identified

  6. Model Credibility Plan: Challenges & Opportunities • Challenges • Circadian model and network simulation codes are being developed by different groups (UMass, Princeton) using different tools (MATLAB, FORTRAN) • UMass work is being performed by a first-year Ph.D. student • Need other third-party evaluators • Opportunities • Partner with other newly funded circadian project: Multiscale Modeling: Circadian Rhythms (Cannon & Dunlap) • Partner with other projects in neural network modeling • Establish new multiscale modeling guidelines for computational neuroscience

  7. Model Credibility Plan: Uniqueness • Modular architecture: single neuron model, cell-to-cell coupling, multicellular model, network reduction and network simulation • Standardization using MATLAB and SBML • Opportunity to coordinate with other IMAG projects in computational neuroscience • Use of funded third-party evaluator outside the MSM consortium

  8. Model Credibility Plan: Crossover with CPMS • CPMS: Credible Practice of Modeling and Simulation in Healthcare • Our short-term goal is to evaluate model-based dosing strategies of benzodiazepine sleep medications for improved adjustment to shift work using mice. • Our long-term goal is to inform clinical practice for prevention and treatment of circadian rhythm disruptions, including mood and sleep disorders and metabolic diseases.

  9. Specific Requirements for Third-Party Evaluators • Knowledge about circadian systems • Interest in coupled oscillators and neural networks • Experience with dynamic model reduction techniques • Experience with MATLAB and SBML • Availability this summer/fall

  10. Questions to IMAG/MSM • Previous experiences with this type of model credibility plan? • Best ways to establish model credibility metrics? • Experience with integrating model components developed with different software tools? • Best ways to work with third-party evaluators? • Knowledge of existing MSM efforts we can leverage? • Experiences with model dissemination?

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