Debusschere earns honors
for sorting out uncertainty
(page 4 of 4)
In perhaps the most promising application to date, Debusschere's group is teaming with researchers at the University of Texas Medical Branch (UTMB) in Galveston. Led by Dr. Allan Brasier, a professor in the Department of Internal Medicine and Institute of Translational Sciences, the UTMB group is investigating the causes of inflammation, an underlying mechanism in diseases such as atherosclerotic heart disease and asthma. They hope to sift out the cell signaling paths inflammation activates. If researchers can decipher these signaling pathways, they may be able to modify them to develop new treatments.
The team has focused on cell signal pathways that govern nuclear factor-κB (NF-κB). NF-κB, a protein complex that regulates the innate immune response, enters the cell nucleus and binds to regulatory DNA sequences. This triggers expression of a network of inflammatory genes, says Brasier, who also is director of UTMB's Sealy Center for Molecular Medicine.
The pathways controlling NF-κB are complex, Brasier says, and can be induced by a number of different substances, including viruses and regulatory proteins and peptides. "All of these pathways activate different subsets of the NF-κB proteins with different kinetics, and are mediated by different intracellular signaling cascades," he says. How much each cell activates NF-κB and responds to it can vary significantly. This variation may have important consequences for the evolution of the inflammatory response.
Brasier says his group already uses biochemical approaches to determine the pathway structures. "Where Bert will have a major impact is to identify the key steps regulating those pathways," he adds.
With a pilot grant from a joint UTMB-Sandia institute, "We're in the process of collecting data and evaluating published models," Brasier says. "Right now, Bert is focusing on identifying which parameters in the models are most important that need to have additional measurements made. This is a repeating process of modeling, experimental observations, refining the models, et cetera."
This type of dynamic understanding of the pathway behavior isn't possible without Debusschere's computational insight, Brasier says.
The methods Debusschere and his fellow researchers have developed also could soon see wider use through an uncertainty quantification toolkit. The methods could help researchers understand how much confidence they can have in results from their computational models.
"We're working on putting together a toolkit that gathers all these things and makes them available to the general user in the (computational science) community," Debusschere says. The group hopes to release it later in 2009 as open-source software.
"The toolkit is something we have worked on with a lot of people in this area," he says. "It's not the product of one specific project but it has contributions from every project that used PCEs."
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