Characterizing the mechanical maturation of the centromere in human cells in the context of aneuploidy and cancer

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PROJECT SUMMARY/ABSTRACT Mitotic fidelity describes a cell's ability to accurately and reliably replicate its genome during cell division. Disrupted mitotic fidelity is a hallmark of cancer, and may significantly impact disease course by selecting for tumor promoting mutations. Thus, the ability to target the mitotic fidelity of cancer cells could be an important therapeutic approach to reducing cancer-associated morbidity and mortality. In order to target mitotic fidelity therapeutically, a clearer understanding of its underlying cellular mechanisms is required. The mechanical characteristics of the centromere, a specialized region of the chromosome that interacts with the mitotic spindle, are likely to be intimately connected to mitotic fidelity. However, centromere biomechanics during mitotic progression have not been quantitatively characterized in unperturbed, living human cells, and so their effect on disease states such as cancer is largely unknown. The central goal of this training proposal is to quantitatively characterize the mechanical characteristics of the centromere in human cells during mitosis and in the context of cancer. I hypothesize that when mitotic fidelity is maintained, there is a signature mechanical maturation of the centromere, and that aneuploidy impairs this process. My preliminary data demonstrates that I have the methods in hand to pursue my goal, and strong support for my central hypothesis. For this fellowship, I propose to test my central hypothesis through two specific aims, each examining a different mechanistic aspect of centromere mechanical maturation and its relationship with aneuploidy. Importantly, both of these aims will provide foundational training experiences in asking mechanistic basic science questions and addressing them through quantitative research methods. The findings obtained from this research will provide the groundwork for a mechanistic model of centromere mechanical maturation and its relationship with aneuploidy in the context of cancer. This model will central in future studies aimed at determining how physical forces during mitosis shape clinical outcomes. Moreover, the proposal provides unique learning opportunities in applying quantitative methodologies to biomedical questions with significant clinical relevance, the core goal of my training as a quantitative physician scientist.