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

项目总结/摘要 有丝分裂保真度描述了细胞在细胞分裂期间准确和可靠地复制其基因组的能力。 有丝分裂保真度的破坏是癌症的标志，并且可能通过选择 肿瘤促进突变。因此，靶向癌细胞的有丝分裂保真度的能力可能是一个重要的因素。 降低癌症相关发病率和死亡率的治疗方法。为了达到有丝分裂的精确性 在治疗上，需要更清楚地了解其潜在的细胞机制。机械 着丝粒的特征，染色体的一个专门区域，与有丝分裂相互作用， 纺锤体，可能与有丝分裂的保真度密切相关。然而，着丝粒生物力学在 有丝分裂进程尚未在未受干扰的活的人类细胞中定量表征，因此它们的 对诸如癌症的疾病状态的影响在很大程度上是未知的。 本培训建议的中心目标是定量表征的机械特性， 在有丝分裂和癌症的背景下，人细胞中的着丝粒。我假设当有丝分裂的忠实性 保持，有一个标志性的机械成熟的着丝粒，而非整倍性损害这一点， 过程我的初步数据表明，我有方法在手，追求我的目标，和强大的 支持我的核心假设。对于这个奖学金，我建议通过两个测试我的中心假设 具体的目的，每个研究不同的机械方面的着丝粒机械成熟及其 与非整倍体的关系重要的是，这两个目标将提供基础培训经验， 提出机械的基础科学问题，并通过定量研究方法解决这些问题。 本研究的结果将为着丝粒的机理模型奠定基础 机械成熟及其与癌症背景下的非整倍体的关系。该模型将在 未来的研究旨在确定有丝分裂过程中的物理力如何影响临床结果。而且 该提案提供了独特的学习机会，将定量方法应用于生物医学问题 具有重要的临床相关性，这是我作为一名定量医生科学家的核心目标。

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.