Joel R. Stiles, M.D. Ph.D.
Adjunct Associate Professor, Neuroscience, Computational Biology- M.D. University of Kansas (1991)
- Ph.D. University of Kansas (1990)
- Office: 300 South Craig, Pittsburgh Supercomputing Center
- Telephone:412-268-4786
- Fax:412-268-8200
- E-mail: stiles@psc.edu
- Website: http://www.psc.edu/~stiles
Spatially realistic simulations of neurotransmitter release, synaptic transmission and plasticity.
Research Summary:
In my laboratory we do a combination of large-scale software development and application to computational neurophysiology.
Software development:
MCell (Monte Carlo cell) is used to simulate the stochastic movements and reactions of molecules within and between cells, e.g., synaptic microphysiology.
PSC_DX is a large visual programming and development environment. It uses a very general and powerful data model, which is especially advantageous for spatially realistic cell modeling.
DReAMM (Design, Render, and Animate MCell Models) is used to edit and visualize MCell and other 3-D models.
Presynaptic calcium dynamics and neurotransmitter release:
Using DReAMM and computer-aided-design software we develop realistic models of active zones within a nerve terminal. Using these models, we run MCell simulations of nerve excitation, calcium influx and binding, and neurotransmitter release. We constrain and validate the model using experimental data (e.g., calcium imaging in collaboration with Steve Meriney), and use the simulations to make quantitative predictions for spatial and functional relationships between calcium channels, calcium binding sites, synaptic vesicles, and other components of active zone architecture. Ongoing work includes simulation of paired pulse facilitation to develop a quantitative model of short-term synaptic plasticity.
Biophysical factors underlying the variability of synaptic signals:
This project includes collaborators in the Computational Neurobiology Laboratory at the Salk Institute and the National Center for Microscopy and Imaging Research at the University of California San Diego. Many spatial and chemical kinetic factors contribute to the variability of synaptic signals, and MCell simulations can be used to investigate their importance in different systems. Synaptic ultrastructure must be reconstructed, and then spatial and kinetic parameters are varied to determine their impact.
In the clinical setting, derangement of synaptic structure and function contributes to the etiology of many diseases, including neurodegenerative movement disorders (e.g., Parkinson's), dementias (e.g., Alzheimer's), affective disorders (e.g., bipolar or major depression), and neuromuscular diseases (e.g., Myasthenia Gravis, Lambert Eaton Syndrome, Slow Channel or AChE deficiency myasthenic syndromes).
Selected Publications:
Wachman, E.S., Poage, R.E., Stiles, J.R., Farkas, D.L., and Meriney, S.D. Spatial distribution of calcium entry evoked by single action potentials within the presynaptic active zone. J. Neurosci. 24:2877-2885, 2004.
Stiles, J.R., Ford, W.C., Pattillo, J.M., Deerinck, T.E., Ellisman, M.H., Bartol, T.M., and Sejnowski, T.J. Spatially realistic computational physiology:
past, present, and future. In: Parallel Computing: Software Technology, Algorithms, Architectures & Applications, ed. Joubert, G, et al. Elsevier, Amsterdam, pp. 685-694, 2004.
Coggan, J.S., Bartol, T.M., Esquenazi, E., Stiles, J.R., Lamont, S., Martone, M.E., Berg, D.K., Ellisman, M.H., and Sejnowski, T.J. Evidence for ectopic neurotransmission at a neuronal synapse. Science 309:446-451, 2005.
Cannon, R.C., Gewaltig, M.C., Gleeson, P., Bhalla, U., Cornelis, H., Hines, M.E., Howell, F.W., Muller, E., Stiles, J.R., Wils, S., and De Schutter, E. Interoperability of neuroscience modeling software: current status and future directions. Neuroinformatics. (in press, 2007)