| Project Detail |
Targeted Research Initiative for Pole Organization Leveraging Experiment and Simulation (TRIPOLES). The mitotic spindle is responsible for segregating chromosomes into two identical sets prior to cell division. Errors in the process can result in daughter cells having an incorrect number of chromosomes, a disorder referred to as aneuploidy. Cells with multipolar spindles, an aberrant spindle architecture marked by three or more spindle pole bodies rather than the typical two, are particularly susceptible to making the mistakes that lead to aneuploidy. However, relatively little is known about the mechanisms involved in multipolar mitotic spindles or how cells regulate them. In this proposal, we will develop a new theoretical framework that models multipolar mitotic spindles with an unprecedented level of detail. The model will incorporate multiple centrosomes with microtubules emanating from them, explicit chromosome pairs with a severable link, and different species of motor and crosslinking proteins to generate forces. We will first use the model to recreate healthy bipolar spindles, then expand it to investigate tripolar spindle dynamics and how cells regulate excess centrosomes. Our model will use first-principle mechanisms, which will allow us to make predictions that can be tested in experiment by our collaborators. By using theory to motivate specific follow-up experiments in this way, we can uncover novel mechanisms involved in the regulation of mitotic spindles that would otherwise go unnoticed. Beyond three main research objectives, this proposal also includes measures for a two-way transfer of knowledge, effective communication and dissemination of results, and overall management of the project. The work done in this proposal has the potential to not only illuminate how cancer cells regulate their aberrant spindle geometries, but also provide fundamental insight into how healthy bipolar spindles transition into unhealthy architectures. |
