Cellular machinery is more complex than any technology humans have understood. Comprehending how this machinery self-assembles and works requires synthesizing interactions between molecular parts of cells into functional mechanistic models. Intelligent design of medical interventions requires this. The only tool capable of this synthesis is mathematical models solved on computers. Detailed case studies of particular cell biological phenomena, not abstract rhetoric, will sharpen this tool and prove its worth. The proposed Center of Excellence at Friday Harbor Laboratories will assemble a cross-disciplinary group of 14 scientists plus staff with this mission: to combine experiment and theory with computational modeling techniques the proposers have helped pioneer into detailed case studies of genetic networks operating in two different contexts-developmental pattern formation and cytoskeletal dynamics, and to promulgate this approach, and the tools supporting it. These studies will consolidate and extend the proposers' current efforts to comprehend: 1) how modules of cross-regulatory genes, installed identically in each cell in an embryo, form and stabilize spatio-temporal gene expression patterns causing cell determination; and 2) how biochemical and mechanical interactions among major cytoskeletal filament systems, molecular motors, cell adhesion proteins, and their myriad regulators cause cells to reorganize their internal components, move, change shape, and divide. Recruiting long-term salaried post-does and visiting sabbatical scientists to the Center and collaborating with them to make models of these phenomena, will teach them to wed computational modeling and experiments to comprehend biological complexity. Center outreach activities will include: 1) Perfecting and publishing computational methods for making and analyzing models of regulatory and cytoskeletal networks; 2) """"""""Hardening' and disseminating our software for building and analyzing gene network models, and for segmenting/visualizing 3D cytoskeletal structure from scanning confocal microscope data; 3) Teaching yearly research apprenticeship courses to recruit biology undergraduates early to careers combining theory, experiment and computation; 4) Hosting teaching workshops and round-table symposia to broadcast the Center's computational modeling successes, facilitate cross-breeding exchange with other scientists and recruit potential converts.
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