Structural mechanisms of centriole assembly during cell duplication

从胚胎到成年，以及我们生命的每一天，我们都依赖于数百万细胞的正常生长和分裂。对于每一次细胞分裂，我们的遗传物质，包装在染色体中，也必须正确地分裂。在人类和动物中，这是通过一种称为核纺锤体的复杂结构实现的，这种结构由细胞两端中心体的拷贝组织而成。分裂后，每个新细胞只有一个中心体；因此，为了进一步的细胞分裂，它必须复制。中心体复制是一个我们所知相对较少的过程。我们知道这个过程中的任何异常都可能导致疾病甚至癌症；然而，我们不知道这个过程是如何调节的，每个中心体成分的作用是什么，或者它们是如何组合在一起的。如果我们能够理解中心体复制是如何发生的以及异常是如何发生的，那么我们就有可能设计出治疗方法或新药。因此，在尽可能详细的层次上理解这一过程是很有意义的。我们建议使用多种方法，包括细胞生物学，显微镜和生物物理学来回答有关中心体复制过程的具体问题。我们感兴趣的是它们精致的9倍对称形状是如何定义的，以及这是否在所有生物体中都是通过相同的方法实现的，或者是否存在显着差异。我们想研究细胞如何控制复制过程的开始，以确保每次细胞分裂只发生一次。最后，我们的目标是找到各种中心体成分在组装中的正确位置，类似于拼图中的碎片。中心体是一个分子机器，由许多大的蛋白质组成。为了能够足够详细地研究这些成分，我们首先旨在找到更小的功能亚基，我们可以用生物物理工具对其进行分析。然后，我们可以根据这些单个片段对整个组件的特性进行预测，并使用电子显微镜和细胞生物学对这些预测进行测试。这项工作的一些重要方面需要我们核心团队没有的专业知识。因此，我们与英国和国外的国际知名团体合作，以获得尽可能广泛的专业知识基础。

From embryo to adulthood and every day of our lives we rely on the normal growth and division of millions of cells. For each cell division our genetic material, packed in chromosomes, must also properly divide. In humans and animals this is achieved by an elaborate structure, called the nuclear spindle, organized by copies of the centrosome at each end of the cell. After division, each new cell has only one centrosome; therefore it must duplicate in order for further cell divisions to occur. Centrosome duplication is a process for which we have relatively little information. We know that any abnormalities in this process can cause diseases or even cancer; however we do not know how this process is regulated, what is the role of each individual centrosomal component or how they assemble together. If we could understand how centrosome duplication takes place and how abnormalities can occur, then we could possibly devise treatments or new drugs. Therefore, there is much interest in understanding this process at the most detailed level possible.We propose to use a combination of approaches, including cell biology, microscopy and biophysics to answer specific questions about the centrosome duplication process. We are interested in how their elaborate 9-fold symmetric shape is defined, and whether this is achieved by the same method in all organisms or whether there are significant differences. We would like to study how the cells control the start of the duplication process to ensure that it only happens once per cell division. Finally, we aim to find the correct place in the assembly for the various centrosomal components, similar to pieces in a puzzle. The centrosome is a molecular machine, composed of many large proteins. To be able to study these components in sufficient detail, we first aim to find smaller, functional subunits, which we can analyze with biophysical tools. We can then make predictions for the properties of whole components based on these individual fragments, and test these predictions using electron microscopy and cell biology. Some important aspects of this work require expertise not present in our core group. Therefore we collaborate with internationally recognized groups in the UK and abroad to access the broadest base of expertise possible.