CAREER: The Biomechanics of Chromosome Movement

Regents Of The University Of Michigan - Ann Arbor, Ann Arbor MI

Investigators

Abstract

The scientific goal of this project is to understand, model, and manipulate the biomechanics of chromosomal separation during cell division. Eukaryotic mitosis depends on molecular machines that move chromosomes along a network of long cylindrical microtubules. This process must be precisely performed and tightly regulated; lack of precision, leading to unequal distribution of genetic material between daughter cells, can result in cell death or other abnormalities. This project approaches this problem from two fronts: 1) computational modeling to predict the character, speed, and dynamics of interactions between chromosomes and microtubules; and 2) biophysical experimentation to test and refine the models. The former approach starts with a simple stochastic, thermodynamic model that describes the origin and coordination of the forces that move chromosomes. Guided by the model, the latter activities focus on the origin and physical properties of chromosome movements. Using an advanced optical gradient trap (optical tweezers) to manipulate microtubules interacting with chromosomes in vitro, forces and mechanical properties will be measured. Complementary experiments will examine chromosome movement in vivo by applying technology in which an ultra-short laser pulse creates targeted, localized disruptions within the mitotic apparatus. The changes that result from severing chromosome-bound microtubules and fragments of chromosome will be compared with modeling predictions to elucidate mechanical properties. These experiments will quantify mechanical and force generating properties that allow chromosomes to: 1) bear and respond to tensile loads to maintain connections with microtubules; 2) move along microtubules; 3) move to appropriate location during the different phases of mitosis; and 4) form and maintain connections with the mitotic spindle. Educational goals include integrating research and teaching to encourage students with strong quantitative skills to pursue cell biology problems, and to provide them with a rigorous interdisciplinary background so they excel at this pursuit. Principal aims are the continued development of classes in Quantitative Cell Biology and Cellular and Molecular Biomechanics, developing a laboratory segment to accompany Quantitative Cell Biology, and developing new teaching resources. This includes continued development of an extensive set of Internet resources, which will evolve into the framework for a new undergraduate text in Quantitative Cell Biology, which will be constructed with input from other investigators. This educational plan will have a significant impact on universities' efforts to expand undergraduate training in Biomedical Engineering. A major long-term benefit will be improved transfer and application of engineering and physics approaches to cell biology and biotechnology research.