During cell division two complete genomes are mechanically segregated via motions coupled to kinetochore microtubule (kMT) assembly and disassembly. Recently, the extent of molecular-level information relevant to the dynamics of kMTs has increased substantially with the convergence of molecular biology and high- resolution digital light microscopy of living, fluorescent protein-transfected cells. However, the dynamics of single kMTs have yet to be visualized, and so a major challenge is to develop an understanding of the mechanisms that regulate individual kMTs. Three important questions regarding kMTs and their regulation remain unanswered: 1) How do molecular components interact to achieve the overall force balance in the mitotic spindle? 2) Are plus-end directed molecular motors the main controllers of kMT assembly and chromosome congression across phylogeny and in human cells? 3) What are the nanoscale-kHz dynamics of kMT plus-ends at the kinetochore? In each case we will establish a mathematical foundation based on physical principles, implement a computer code, and compare the simulation predictions to experimental microscopy data using model-convolution to rigorously test specific hypotheses. The project will build on existing collaborations with the Bloom, Cassimeris, Salmon, and Winey/O'Toole groups, will develop new collaborations with the Berman and Hays groups, and will allow biomedical engineers to develop models in close collaboration with cell biologists so that hypotheses will be quantitatively tested against experimental data. Furthermore, the simulations will facilitate the design and development of new experiments for more effective hypothesis testing. In the end, we will combine theory with experiment to better understand the biophysical basis of MT dynamics during mitosis and associated chromosome movements. The knowledge gained through these studies will ultimately be useful in clinical applications, such as cancer treatment, because of the centrality of mitotic spindle dynamics to mitosis. Some of the more effective cancer treatments, such as taxol (paclitaxel), are based on their interference with MT-based processes during cell division. In addition, some of the proteins to be investigated, such as kinesin-5, are the targets of novel cancer therapeutics. Understanding MT dynamics and their regulation by microtubule associated proteins in mitosis will allow us to more rationally develop new cancer treatment strategies. This project will facilitate the development of a group of engineers who are interested in applying mathematics and physics to address fundamental cell biology questions in close collaboration with cell biologists. Ultimately we are driving toward reliable, predictive models for the molecular-level control of mitotic spindles so that we can control cancer progression.
Once chromosomes are replicated, they need to be properly segregated into each of two daughter cells. We will study the catastrophe dynamics of the """"""""microtubule"""""""" polymers that drive proper chromosome segregation. These studies will give new insight into how cells become cancerous, and how to prevent cancer cells from proliferating.
|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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