Computational and Experimental Studies of Microtubule Dynamics and Regulation by Binding Proteins

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Intellectual merit. Microtubules (MTs) are the primary components of crucial subcellular structures including the intracellular transport network and the mitotic spindle that separates the chromosomes during cell division. A central problem in cell biology is to understand how these MT-based structures form, are dynamically maintained, and drive the organization of the rest of the cell. Classically, these questions have been addressed by identifying and characterizing the proteins that regulate MT dynamics. While this approach has been powerful, it is not sufficient: the MT cytoskeleton is a complex system that exhibits behaviors ("emergent properties") not straightforwardly predictable from analysis of the individual components. Such a system level problem requires system level approaches: mathematical and computational modeling. The goals of this project are to develop, utilize, and experimentally test two computational models of MT dynamics, and to use these models to investigate the function and mechanism of MT binding proteins. These models will be built at two scales: a mesoscopic (medium scale) model that will be used to investigate the intrinsic properties of a system of dynamic MTs in a cell-like environment, and a molecular scale model that will be used to develop hypotheses about the mechanisms of dynamic instability and its alteration by MT binding proteins. The long-term goal of this work is to develop a predictive and quantitative understanding of the MT cytoskeleton and its regulation by MT binding proteins, which will impact fields ranging from systems biology to nanotechnology. Broader impacts. An important part of this project is to develop a freely disseminated software suite "MT Toolbox" (MTT), which will include analysis tools and instructional electronic tutorials. MTT will have two implementations: 1) a web-based interface that will allow scientists and students at remote sites to submit jobs for running the models and their analysis tools on our server; 2) a freely disseminated software suite containing all programs with online tutorials, user, and programmer's guides. The flexible models and tutorials produced through this project will allow researchers to develop and test specific hypotheses about the mechanisms of MT dynamics, which will in turn help design and direct future experiments. More broadly, it will help students and researchers at all levels gain an intuitive understanding of dynamic MT systems. The project will educate three graduate students and two undergraduates who will benefit from interdisciplinary training in biology and computational modeling. Projects related to the proposed research will be incorporated in The Research Experience for Teachers at Notre Dame (RET@ND) program as well as the Notre Dame McNair Program, which promotes graduate and doctoral studies for minority students.