System-mechanics of the kinetochore: operating principles of a complex mechanochemical engine

动粒系统力学：复杂机械化学发动机的工作原理

基本信息

批准号：
BB/I021353/1
负责人：
Andrew McAinsh
金额：
$ 92.45万
依托单位：
University of Warwick
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2012
资助国家：
英国
起止时间：
2012 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FI021353%2F1
关键词：
System mechanics kinetochore operating principles

项目摘要

Human beings are built from 50 trillion individual cells. Each cell contains 46 chromosomes - the packages of genetic material (DNA), which provide the instructions for how a cell should work and how a whole organism should be built. This huge number of cells originates from a single cell, the zygote, which is the result of fertilization of an egg with a sperm. This single cell needs to be able to divide itself to generate two new daughter cells, which then also divide to produce further cells; this process repeats until the correct number of cells are generated. Moreover, cells do not live forever and are therefore constantly being replaced by new ones. Thus, cell division is fundamental to the existence of life. A key part of cell division involves the accurate separation of the chromosomes into the two daughter cells - a process called mitosis. It is crucial that each daughter cell receives a complete set of chromosomes. We know that having the wrong number of chromosomes is a cause of multiple human diseases: (1) greater than 80% of human solid tumors have the wrong number of chromosomes and changing chromosome number is known to cause cancer in mice. (2) Many developmental disorders are the result of mistakes in chromosome separation - a well-known example is Downs Syndrome in which cells have an extra copy of chromosome 21. (3) A large proportion of miscarriages are caused by problems in chromosome separation. Clearly, it is vital that we work out how chromosome separation works. To move a chromosome the cell makes use of molecular cables called microtubules that can grow and shrink. Each chromosome has a 'hook' called the kinetochore, which can attach to the end of a microtubule cable. As the cable grows and shrinks the chromosome can be pushed and pulled. This is a beautiful system whereby the cell can move chromosomes around inside itself. However, unlike a hook, the kinetochore is able to control how and when a microtubule cable grows and shrinks. This way the kinetochore is the 'control centre' and the 'engine room' that decides when and where a chromosome moves. Kinetochores move all the 46 chromosomes into a line at the centre of the cell. This is called metaphase. At this time the chromosomes move back-and-forth like the pendulum on a clock, and then, the chromosomes are pulled into the daughter cells. But, how does the kinetochore do this? Why and how do the chromosomes change direction? The experiments that we propose to carry out will help answer these exciting and intriguing question and therefore advance our understanding of how chromosomes are separated into daughter cells during cell division. To do this we will use state-of-the-art imaging technology (microscopes) to observe how chromosomes move in living human cells. We can then accurately measure what happens to how the chromosomes move when we remove parts of the machinery from the cell. Because this is such a complex biological problem we will use mathematics to build a model of how the system works. By combining the disciplines of biology and mathematics together we expect to make large advances in our understanding of chromosome separation.

人类是由 50 万亿个单个细胞构成的。每个细胞包含 46 条染色体——遗传物质 (DNA) 的包装，它提供了细胞如何工作以及整个有机体如何构建的说明。如此大量的细胞起源于单个细胞，即受精卵，它是卵子与精子受精的结果。这个单细胞需要能够自我分裂以产生两个新的子细胞，然后子细胞也分裂产生更多的细胞；重复此过程直到生成正确数量的细胞。此外，细胞不会永远存活，因此会不断被新细胞取代。因此，细胞分裂是生命存在的基础。细胞分裂的一个关键部分涉及将染色体准确分离到两个子细胞中，这一过程称为有丝分裂。每个子细胞接收一套完整的染色体至关重要。我们知道，染色体数目错误是导致多种人类疾病的原因：(1) 超过 80% 的人类实体瘤染色体数目错误，并且已知染色体数目的改变会导致小鼠癌症。 (2) 许多发育障碍是染色体分离错误的结果 - 一个众所周知的例子是唐氏综合症，其中细胞有一个额外的 21 号染色体副本。 (3) 很大一部分流产是由染色体分离问题引起的。显然，弄清楚染色体分离的工作原理至关重要。为了移动染色体，细胞利用了一种称为微管的分子电缆，这种分子电缆可以生长和收缩。每条染色体都有一个称为动粒的“钩子”，它可以附着在微管电缆的末端。随着电缆的生长和收缩，染色体可以被推拉。这是一个美丽的系统，细胞可以在其内部移动染色体。然而，与钩子不同的是，动粒能够控制微管电缆生长和收缩的方式和时间。这样，动粒就是“控制中心”和“发动机室”，决定染色体何时何地移动。动粒将所有 46 条染色体移动到细胞中心的一条线上。这称为中期。此时，染色体就像钟摆一样来回移动，然后，染色体被拉入子细胞中。但是，着丝粒是如何做到这一点的呢？染色体为什么以及如何改变方向？我们打算进行的实验将有助于回答这些令人兴奋和有趣的问题，从而增进我们对细胞分裂过程中染色体如何分离成子细胞的理解。为此，我们将使用最先进的成像技术（显微镜）来观察染色体如何在活人类细胞中移动。然后，我们可以准确地测量当我们从细胞中移除部分机器时染色体如何移动。因为这是一个非常复杂的生物学问题，我们将使用数学来构建系统如何工作的模型。通过将生物学和数学学科结合在一起，我们期望在对染色体分离的理解上取得巨大进展。