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

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INTELLECTUAL MERITThe goal of this project is to use coordinated experiment and computational modeling to answer fundamental questions about the system-level behavior of the microtubule cytoskeleton. Microtubules (MTs) are the primary components of crucial subcellular structures including the mitotic spindle, which segregates the chromosomes, and the intracellular transport network, which organizes the cytoplasm. Understanding how MT-based structures assemble, are maintained, and drive cell organization is a central problem in cell biology. MTs exhibit a surprising behavior known as dynamic instability -- individual MT fibers transition randomly between extended phases of growth and depolymerization. The long-term goal of this project is to establish an understanding of DI and its regulation by MT binding proteins by coupling experiment with iterative multi-scale modeling. The specific goals of this research are: 1) Obtain an understanding of, and seek to establish, a set of general principles for how MT binding proteins cooperate to modulate MT dynamics and polymer mass using MT plus-end tracking proteins as a model; 2) Define the relationship between the behavior of the bulk MT polymer and that of individual MTs. A key goal is to use modeling approaches to investigate and refine classical theories of equilibrium polymers that define MT dynamics. While the focus is on MTs, the improved understanding should be relevant to other cytoskeletal polymers; 3) Develop freely disseminated software packages with associated tools and instructional electronic tutorials to help students and researchers gain an intuitive understanding of dynamic MT systems using computational models of MT assembly. BROADER IMPACTSThis projects combined modeling and experimental effort will help students and researchers at all levels gain an intuitive understanding of dynamic MT systems. This understanding is important for applications ranging from nanotechnology (the mitotic spindle is a striking example of a self-organized nanotechnological system) to controlling agricultural pests (some prominent antiparasitic and antifungal compounds are directed at MTs). The PIs will integrate the software tools developed as part of this project into their classes. The project will also educate graduate and undergraduate students who will benefit from interdisciplinary training in biology and computational modeling. Projects related to this research will be incorporated in The Research Experience for Teachers at Notre Dame program as well as into programs promoting graduate and doctoral studies for minority students.