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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50万亿个单独的细胞组成的。每个细胞包含46条染色体--遗传物质(DNA)的包装，它为细胞如何工作以及整个有机体应该如何构建提供了指令。这些数量巨大的细胞来自单个细胞，即受精卵，这是卵子与精子受精的结果。这个单个细胞需要能够自我分裂以产生两个新的子细胞，然后这两个子细胞也会分裂以产生更多的细胞；这个过程重复，直到产生正确的细胞数量。此外，细胞不会永远存活，因此不断地被新的细胞取代。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地分离成两个子细胞--这一过程被称为有丝分裂。至关重要的是，每个子细胞都要收到一套完整的染色体。我们知道，染色体数目错误是导致多种人类疾病的原因之一：(1)超过80%的人类实体肿瘤的染色体数目错误，并且已知染色体数目的变化会导致小鼠癌症。(2)许多发育障碍是染色体分离错误的结果--一个著名的例子是唐斯综合症，即细胞有额外的21号染色体拷贝。(3)很大比例的流产是由染色体分离问题引起的。显然，我们弄清楚染色体分离是如何工作的是至关重要的。为了移动染色体，细胞利用被称为微管的分子电缆，可以生长和收缩。每条染色体都有一个名为动粒的‘钩’，它可以连接到微管电缆的末端。随着缆索的生长和收缩，染色体可以被推动和拉动。这是一个美丽的系统，通过这个系统，细胞可以在自身内部移动染色体。然而，与钩不同的是，动粒能够控制微管电缆的生长和收缩的方式和时间。这样，着丝粒就是决定染色体何时何地移动的“控制中心”和“引擎室”。着丝点将所有46条染色体移到细胞中心的一条线上。这就是中期。此时，染色体像时钟上的钟摆一样来回移动，然后，染色体被拉入子细胞。但是，动毛虫是如何做到这一点的呢？为什么以及如何改变染色体的方向？我们计划进行的实验将有助于回答这些令人兴奋和耐人寻味的问题，从而加深我们对染色体在细胞分裂过程中如何分离成子细胞的理解。为了做到这一点，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的人类细胞中移动。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，染色体如何移动的情况。因为这是一个如此复杂的生物学问题，我们将使用数学来建立一个系统如何工作的模型。通过将生物学和数学的学科结合在一起，我们希望在我们对染色体分离的理解上取得重大进展。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Esperanto for histones: CENP-A, not CenH3, is the centromeric histone H3 variant.

DOI：
10.1007/s10577-013-9347-y
发表时间：
2013-04
期刊：
CHROMOSOME RESEARCH
影响因子：
2.6
作者：
Earnshaw, W. C.;Allshire, R. C.;Black, B. E.;Bloom, K.;Brinkley, B. R.;Brown, W.;Cheeseman, I. M.;Choo, K. H. A.;Copenhaver, G. P.;DeLuca, J. G.;Desai, A.;Diekmann, S.;Erhardt, S.;Fitzgerald-Hayes, M.;Foltz, D.;Fukagawa, T.;Gassmann, R.;Gerlich, D. W.;Glover, D. M.;Gorbsky, G. J.;Harrison, S. C.;Heun, P.;Hirota, T.;Jansen, L. E. T.;Karpen, G.;Kops, G. J. P. L.;Lampson, M. A.;Lens, S. M.;Losada, A.;Luger, K.;Maiato, H.;Maddox, P. S.;Margolis, R. L.;Masumoto, H.;McAinsh, A. D.;Mellone, B. G.;Meraldi, P.;Musacchio, A.;Oegema, K.;O'Neill, R. J.;Salmon, E. D.;Scott, K. C.;Straight, A. F.;Stukenberg, P. T.;Sullivan, B. A.;Sullivan, K. F.;Sunkel, C. E.;Swedlow, J. R.;Walczak, C. E.;Warburton, P. E.;Westermann, S.;Willard, H. F.;Wordeman, L.;Yanagida, M.;Yen, T. J.;Yoda, K.;Cleveland, D. W.
通讯作者：
Cleveland, D. W.

Exotic mitotic mechanisms.