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

错误着丝粒-微管附着的形成和纠正机制

基本信息

批准号：
2596911
负责人：
金额：
--
依托单位：
University of Warwick
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=studentship-2596911
关键词：
Mechanisms governing formation correction erroneous

项目摘要

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.

细胞分裂是一项重要但有风险的事情。借助纺锤体（一种双极引导支架），复制的染色体在两个新细胞之间分离，该纺锤体通过动粒与每条染色体连接。动粒是自我校正的分子机器，产生移动染色体的力。他们还能够识别并消除不正确的着丝粒-纺锤体附件。这是关键，因为错误附着的持续存在可能导致新细胞获得或丢失整个染色体，称为非整倍性，与生殖失败、衰老和癌症有关。在这个项目中，学生将调查不正确附件的生命周期，重点是 Syntelics；在这种情况下，复制染色体对上的动粒附着在同一纺锤体极（而不是相反的极）上。他们将跟踪动粒构象、附着和磷酸化状态，并创建一个从创建到解决这些不正确附着的事件模型。为了实现这一目标，学生将利用并获得以下方面的丰富经验：先进的荧光显微镜技术，包括固定细胞转盘共聚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望这种组合细胞和计算生物学为人类细胞如何确保维持正确的染色体数量提供了新的见解。