Mechanisms of spindle checkpoint silencing

这个项目是关于了解细胞如何确保染色体平等地分离到子细胞。人类是由大约100万亿个单个细胞组成的。每个细胞包含46条染色体，其中包装了我们的遗传物质(DNA，脱氧核糖核酸)，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，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，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，染色体数目错误是多种人类疾病的原因之一，最明显的是癌症，超过80%的人类肿瘤的染色体数目错误。事实上，在老鼠身上实验改变染色体数量已经被证明会导致癌症。其次，许多发育障碍是染色体分离错误的结果，例如唐斯综合症，细胞有额外的21号染色体拷贝。很大一部分流产也是由染色体分离问题引起的。显然，弄清楚染色体分离过程是如何控制的，以及为什么这些控制在这些疾病中是有缺陷的或被覆盖的，这一点显然至关重要。每条染色体由两个姐妹染色单体组成，在细胞复制DNA后，这两个染色单体粘在一起。为了分离这两个姐妹染色单体(两个子细胞各一个)，细胞利用被称为微管的分子电缆。每个姐妹染色单体都有一个名为动粒的“钩”，它可以连接到微管电缆的末端。随着连接到两个姐妹染色单体的电缆的生长和缩小，染色体在细胞内四处移动。这种相互挤压的运动允许染色体在细胞中央排成一条线。当一切准备就绪后，连接两个姐妹染色单体的胶水被移除，姐妹染色单体被拉到相对的子细胞。但这个过程是如何控制的？事实证明，动粒也是一个监控系统的控制中心，这个系统被称为纺锤体组件检查点，它确保姐妹染色单体在配对过程完成之前不会分离。我们最近发现了这个过程中的核心角色，但我们还不知道它们是如何控制的，也不知道这个系统是如何运作的。我们将要做的实验将有助于回答这些令人兴奋和有趣的问题，从而促进我们对染色体在细胞分裂过程中如何平等地分离到子细胞的理解。为了做到这一点，我们将使用最先进的成像技术(强大的显微镜)以及分子遗传学和生物化学的现代技术来观察染色体如何在活细胞中移动，以及相关因素是如何发挥作用的。这些问题的答案将有助于确定抗击疾病的新目标和治疗方法。

This project is about understanding how cells ensure chromosomes are segregated equally to daughter cells. Human beings are built from around 100 trillion individual cells. Each cell contains 46 chromosomes into which is packaged our genetic material (DNA, deoxyribonucleic acid), which provides 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 that 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 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, most notably cancer where greater than 80% of human tumors have the wrong number of chromosomes. Indeed, altering chromosome number experimentally in mice has been shown to cause cancer. Secondly, many developmental disorders are the result of mistakes in chromosome separation such as Downs Syndrome, in which cells have an extra copy of chromosome 21. A large proportion of miscarriages are also caused by problems in chromosome separation. It is clearly vital that we work out how the process of chromosome segregation is controlled and why these controls are defective or over-ridden in these diseases. Each chromosome is made up of two sister chromatids that are stuck together after the cell replicates its DNA. To separate these two sister chromatids (one to each of the two daughter cells), the cell makes use of molecular cables called microtubules. Each sister chromatid has a "hook" called the kinetochore, which can attach to the end of a microtubule cable. As the cables attached to the two sister chromatids grow and shrink the chromosomes are moved around inside the cell. This jostling motion allows the chromosomes to line up in the middle of the cell. When everything is ready, the glue joining the two sister chromatids is removed and the sister chromatids are pulled to opposite daughter cells.But how is this process controlled? It turns out that the kinetochore also operates as the control centre for a monitoring system, called the spindle assembly checkpoint, which ensures that sister chromatids do not separate until the alignment process is complete. We have recently discovered the central players in this process but we do not yet understand how they are controlled nor how this system operates.The experiments that we will do will help answer these exciting and intriguing questions and therefore advance our understanding of how chromosomes are separated equally into daughter cells during cell division. To do this we will use state-of-the-art imaging technology (powerful microscopes) and modern techniques in molecular genetics and biochemistry to observe how chromosomes move in living cells and how the factors involved operate. The answers to these questions will help the identification of new targets and therapies to combat disease.