In cell division the actions of many molecules are integrated to mechanically segregate two complete genomes from each other via motions directly coupled to the dynamics of kinetochore microtubules. The extent of molecular-level-information relevant to cell division has increased substantially with the convergence of molecular biology and high-resolution digital light microscopy of living fluorescent protein- transfected cells. A major challenge now is to develop an understanding of cellular-level mechanisms from the vast amounts of quantitative molecular-level data. Importantly, the dynamic behavior of individual kinetochore microtubules remains to be determined. Fortunately, advances in high-speed computing make it increasingly practical to model complex processes such as microtubule dynamic instability and associated chromosome motions. The objective of this project will be to develop computer-based models to test hypotheses for the mechanisms controlling kinetochore microtubule dynamics in mitosis. Specifically, we will develop computational models to predict the separate and combined effects of motor-based polar ejection forces, stable chemical gradients, and mechanical tension in budding yeast mitosis. We will also develop reaction-diffusion models that generate the hypothesized chemical gradients, develop a theory for microtubule behavior in such gradients, and test the theory in LLCPK cells. In addition, we will develop an integrated mechanochemical model of microtubules embedded in the budding yeast kinetochore and test how mechanical force on the kinetochore can affect microtubule stability. In all cases models will be developed in ongoing collaborations with cell biologists, and the predictions compared directly to experimental observations. To facilitate these quantitative comparisons, we will implement models of high- resolution light microscopy to produce synthetic digital images of the fluorescent molecules in living cells and directly compare the model-predicted statistics to those obtained experimentally. ? ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Deatherage, James F
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University of Minnesota Twin Cities
Biomedical Engineering
Schools of Engineering
United States
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Castle, Brian T; McCubbin, Seth; Prahl, Louis S et al. (2017) Mechanisms of kinetic stabilization by the drugs paclitaxel and vinblastine. Mol Biol Cell 28:1238-1257
Tubman, Emily S; Biggins, Sue; Odde, David J (2017) Stochastic Modeling Yields a Mechanistic Framework for Spindle Attachment Error Correction in Budding Yeast Mitosis. Cell Syst 4:645-650.e5
Cekan, Pavol; Hasegawa, Keisuke; Pan, Yu et al. (2016) RCC1-dependent activation of Ran accelerates cell cycle and DNA repair, inhibiting DNA damage-induced cell senescence. Mol Biol Cell 27:1346-57
McCoy, Kelsey M; Tubman, Emily S; Claas, Allison et al. (2015) Physical limits on kinesin-5-mediated chromosome congression in the smallest mitotic spindles. Mol Biol Cell 26:3999-4014
Prahl, Louis S; Castle, Brian T; Gardner, Melissa K et al. (2014) Quantitative analysis of microtubule self-assembly kinetics and tip structure. Methods Enzymol 540:35-52
Hepperla, Austin J; Willey, Patrick T; Coombes, Courtney E et al. (2014) Minus-end-directed Kinesin-14 motors align antiparallel microtubules to control metaphase spindle length. Dev Cell 31:61-72
Castle, Brian T; Odde, David J (2013) Brownian dynamics of subunit addition-loss kinetics and thermodynamics in linear polymer self-assembly. Biophys J 105:2528-40
Coombes, Courtney E; Yamamoto, Ami; Kenzie, Madeline R et al. (2013) Evolving tip structures can explain age-dependent microtubule catastrophe. Curr Biol 23:1342-8
Hendricks, Adam G; Lazarus, Jacob E; Perlson, Eran et al. (2012) Dynein tethers and stabilizes dynamic microtubule plus ends. Curr Biol 22:632-7
Seetapun, Dominique; Castle, Brian T; McIntyre, Alistair J et al. (2012) Estimating the microtubule GTP cap size inýývivo. Curr Biol 22:1681-7

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