Computational Modeling and Analysis of Kinetochore Dynamics during Mitosis

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DESCRIPTION (provided by applicant): During mitosis, chromosomes are aligned so that they can be properly segregated by the mitotic spindle. Proper chromosome alignment and subsequent separation during mitosis is critical in preventing aneuploidy, a condition in which chromosomes are not equally segregated. Aneuploidy has been implicated in tumorigenic transformation of cells in vitro, and is commonly observed in human cancer cells. While it is known that microtubules regulate the alignment of chromosomes during mitosis, a mechanistic understanding of how the dynamics of multiple microtubules associated with each individual chromosome are coordinated to achieve proper chromosome alignment remains elusive. To establish a solid theoretical framework to redefine and shift key questions in the field of mitosis, specifically as applied to the coordination and regulation of multiple microtubules associated with each individual chromosome, we will develop a predictive, stochastic computational model, and perform experiments to test predictions of the model. We will exploit Candida albicans as a model system because it has the unique property that it can be manipulated to undergo mitosis with either a single microtubule attachment per chromosome, or with multiple microtubule attachments per chromosome. Specifically, we will (1) establish the 3D geometry of the C. albicans mitotic spindle using electron microscopy methods, (2) develop a stochastic computational model for the wild-type C. albicans mitotic spindle, and (3) leverage the C. albicans predictive computational model for hypothesis testing. While it has been shown that aberrant microtubule dynamics lead to chromosomal instability, our studies will distinguish whether it is likely that the coordination of the microtubule dynamics are important for the fidelity of chromosome segregation during mitosis, or whether regulation of microtubule dynamics allows for proper chromosome attachment turnover. Because many significant chemotherapy drugs act to stop mitosis by disrupting microtubule dynamics, an improved understanding for the role of microtubule dynamics in regulating chromosome dynamics will provide a new context for interpreting the mechanism of action for important chemotherapy drugs. In general, this project will provide an important example of how quantitative modeling can be integrated with experiments at the earliest stages of investigation, such that computational modeling will not only be used to test hypotheses, but will also be used to design experiments and refine specific hypotheses as the project proceeds. PUBLIC HEALTH RELEVANCE: In this project, we seek to understand how chromosomes are properly aligned and segregated during cell division. Proper chromosome alignment and subsequent separation during mitosis is critical in preventing aneuploidy, a condition in which chromosomes are not equally segregated. Aneuploidy has been implicated in birth defects such as Down syndrome, and is commonly observed in human cancer cells.