Title: Stochastic Modeling of EGFR/ErbB Signaling Pathways with Spatial Resolution and Single Molecule Details

Speaker: Genie Hsieh, UNM Electrical and Computer Engineering Dept

Date/Time: Tuesday, September 2, 2008, 2:30 p.m.

Location: CSRI Building, Room 90 (Sandia NM)

Brief Abstract: Many activities of cells are controlled by cell surface receptors, which respond to ligands by triggering intracellular signaling reactions. Improved understanding of receptor signaling has a number of potential practical applications, such as the rational design of drugs and vaccines. The process of signaling through receptors involves highly connected networks of interacting components. Understanding the behavior of these networks requires the development of mathematical and computational modeling.

Here, an agent-based simulator is developed in C++ to study diverse molecular interactions in complex signaling pathways with spatial resolution and single molecule detail. It permits stochastic modeling of protein clustering, protein diffusion and biochemical reactions within an idealized cellular geometry. Components diffuse and react with nearby particles in accord with chemical rate reactions. The modularized design confers flexibility.

The model was applied to investigate mechanisms of EGFR homodimerization and activation as functions of time and receptor conformation, density and spatial distribution. Results indicate that receptor density is a principal factor in the ability to form a measurable amount of active homodimers in the absence of ligands. Our results also predict that receptor clustering exacerbates the density-dependent homodimerization of unoccupied receptors. We next considered how the previously observed topographic distributions of three ErbB family members might influence homo and heterodimerization rates. Our spatial model predicts significantly different receptor dimerization patterns from those derived in well-mixed models. This study demonstrates that agent-based, spatially realistic models offer new insight into the roles of membrane architecture on receptor behavior. We are testing the model for interactions of downstream signaling molecules, based in part on spatial constraints of docking partners and on observed patterns of signaling proteins in membranes, which will be a powerful tool for studying growth factor signaling in the context of breast and other cancers.

Bio:  Genie Hsieh is a doctoral student in the UNM Electrical and Computer Engineering Dept. Her dissertation project focuses on studying the mechanism that results in the spatial segregation of signaling molecules at the membrane and how it affects early events in ErbB signaling, which is a powerful inducer of gene transcription involved in endometrial cancer. Ms. Hsieh develops a agent-based, stochastic model to simulate diffusion, clustering and activation of receptors in the plasma membrane. She is a STMC (Center for the Spatiotemporal Modeling of Cell Signaling Networks) fellow. She earned a master's degree in Computer Engineering at UNM and a B.S. degree in Computer Science at the National Taiwan University, Taiwan.

CSRI POC: Jim Ang, (505) 844-0068