Project Title: Monte Carlo Methods for Simulating Microphysiology
Rozita Laghaei, PSC Research Scientist
Computational modeling is becoming very important in different fields of science. The ability to use modeling and simulation is a core competency that many undergraduate students need to develop. New technology and computational approaches permit modeling of increasingly complicated biological systems. For example, the cell modeling software MCell uses Monte Carlo algorithms to track the evolution of biochemical events in space and time for individual molecules. Details about molecular structures are ignored. Particles move according to a 3D Brownian-dynamics random walk and encounter boundaries and surface molecules as they diffuse which may result in chemical reactions governed by user specified mechanisms. As a case study we use MCell software to provide insight into many experimentally inaccessible aspects of synaptic function and the microscopic mechanisms underlying Ca2+ triggered synaptic vesicle release. The stochastic computational modeling using MCell can also be used to model and evaluation of a novel treatment for Lambert-Eaton Myasthenic Syndrome (LEMS), a neuromuscular disease that is characterized by motor nerve terminal weakness. This neurological disease is known to disrupt the normally well-organized active zone (AZ) and reduce the number of presynaptic calcium channels. This autoantibody mediated reduction of presynaptic calcium channels leads to severe muscle weakness.
MCell simulations can be used to evaluate the effects of the current treatment for LEMS (DAP alone which does not provide enough symptomatic relief for patients to return to normal activity and in combination with a newly developed calcium channel gating modifier (GV-58). These drugs are predicted to act synergistically to greatly enhance transmitter release. The use of MCell simulations in drug proper dose determination is an innovative approach that is predicted to extend beyond what can be done with physiological experiments alone.
Students will learn the basics of CellBlender and MCell. The frog and mouse MCell models of neuromuscular junction and synaptic vesicle release mechanism. In collaboration with Dr. Steve Meriney (Neuroscience Dept., University of Pittsburgh) and his lab members they will study the effects of varying the spatial distribution of the voltage-gated Ca2+ channels, stochastic Ca2+ influx, diffusion, and binding. The students will learn how to use supercomputers. The students will learn how to analyze the output of simulations. Finally, we will explain the molecular issues underlying the Lambert-Eaton myasthenic syndrome disease (LEMS). They will explore the mechanisms that might lead to novel LEMS treatment strategies. They will learn to model calcium ion flux during exposure to a potassium channel blocker (DAP) and a calcium channel gating modifier (GV-58) and will study the synergistic effect of these two drugs using our MCell model.
Students will study the synergistic effect of GV-58 plus DAP on LEMS-modified mouse model and predict the proper dosages of the combination of these drugs.
The student will receive a stipend or course credit for this work.
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