Mechanisms governing the formation and correction of erroneous kinetochore-microtubule attachments

细胞分裂是一项基本但有风险的业务。复制的染色体在纺锤体的帮助下在两个新细胞之间分离，纺锤体是一个两极引导支架，通过着丝粒连接到每条染色体。动点是一种自我修正的分子机器，可以产生力量来移动染色体。他们还能够识别和消除不正确的动粒-纺锤体连接。这一点很关键，因为错误附着的持续会导致新细胞获得或丢失整个染色体，即所谓的非整倍体，这与生殖障碍、衰老和癌症有关。在这个项目中，学生将调查错误连接的生命周期，重点放在联会上；在这种情况下，复制的染色体对上的动点连接到相同的纺锤体极(而不是相反的极)。他们将跟踪动粒构象、附着和磷酸化状态，并创建从创建到解决这些错误附着的事件模型。为了实现这一目标，学生将在以下方面利用并获得丰富的经验：先进的荧光显微镜技术，包括固定细胞旋转圆盘共焦显微镜和活细胞晶格光片显微镜。计算建模和分析管道的开发和使用基本的分子生物学技术我们期待细胞和计算生物学的结合为人类细胞如何确保保持正确的染色体数量提供新的见解。

Cell division is an essential but risky business. Duplicated chromosomes are segregated between the two new cells with the aid of the spindle, a bipolar guidance scaffold, which is connected to each chromosome through the kinetochore. Kinetochores are self-correcting molecular machines that generate forces to move chromosomes. They are also able to identify and eliminate incorrect kinetochore-spindle attachments. This is key as persistence of incorrect attachments can lead to new cells gaining or losing entire chromosomes, known as aneuploidy, which is associated with reproductive failure, ageing, and cancer. In this project the student will investigate the life cycle of incorrect attachments with a focus on syntelics; in this situation the kinetochores on a duplicated chromosome pair are attached to the same spindle pole (rather than opposite poles). They will track kinetochore conformation, attachment, and phosphorylation status, and create a model of events from creation to resolution of these incorrect attachments. To achieve this, the student will utilise and gain extensive experience in: Advanced fluorescent microscopy techniques, including fixed cell spinning disk confocal microscopy and live cell lattice light sheet microscopy Development and use of computational modelling and analysis pipelines Essential molecular biology techniquesWe expect this combination of cell and computational biology to provide new insights into how human cells ensure they maintain the correct number of chromosomes.