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Elucidating the role of the nuclear envelope in centriole duplication

阐明核膜在中心粒复制中的作用

基本信息

批准号：
BB/P019188/1
负责人：
Paul Conduit
金额：
$ 56.93万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FP019188%2F1
关键词：
Elucidating role nuclear envelope centriole

项目摘要

Our bodies are made from billions of cells, but we start from just a single fertilised egg that divides into two, then four, then eight cells etc. Once these cells become a functioning organism, many cells continue to divide and help re-generate damaged tissue. Sometimes cell division goes wrong and cells are made that divide uncontrollably, producing cancerous tumours. We are trying to understand cells manage to avoid this.For cells to divide correctly, they must copy their DNA and then separate each copy to opposite sides of the cell, so that when the cell divides into two, each new cell inherits one single copy of the DNA. The copied DNA is pulled apart by molecular "fibres" known as microtubules, and these fibres are formed by spherical objects known as centrosomes. The fibres reach out from one of two centrosomes positioned either side of the DNA and then attach and pull the copied DNA apart.Importantly, each daughter cell inherits only one centrosome, but needs two to be able to divide again. Thus, the centrosome must duplicate itself and this duplication process must not go wrong, as producing too many centrosomes can lead to problems when the cell tries to separate the duplicated DNA, and this may lead to cancer. Our key aim is to understand how centrosome duplication is properly controlled. Centrosomes are composed of a pair of cylindrical-shaped structures known as centrioles. During centrosome duplication, these centrioles split apart to produce two new centrosomes. To ensure that this can happen in the following cell cycle, each centriole must produce a new "daughter" centriole, resulting in a new pair of mother and daughter centrioles in each centrosome. Although under normal conditions only one new daughter centriole is produced during this process, it is possible that multiple daughter centrioles can form on a single mother centriole, and this ultimately results in too many centrosomes being made. Within the cell, centrosomes are tightly associated with a membrane that surrounds the DNA, known as the nuclear envelope. Unexpectedly, we have recently found that daughter centrioles tend to form on the side the mother centriole that faces the nuclear envelope, and when we artificially detach the centrosomes from the nuclear envelope the position of daughter centriole assembly on the mother is randomised. We want to investigate if the local environment between the mother centriole and the nuclear envelope drives daughter centriole assembly. We predict that this may help ensure that one and only one new daughter assembles during each centriole duplication event.We will test this using fruit flies as a model system, as we can easily manipulate their genome to create the ideal conditions for our experiments. Most of the genes in the fly are similar to our own and the process of centriole duplication is very similar in flies and humans. Therefore, what we discover in the fly will be of great importance to understanding human health and disease. We have also established a collaboration with a lab who works with human cell lines, and we will use the information we learn from the fly to investigate how cellular structures such as the nuclear envelope may influence and help control centriole duplication in human cells.

我们的身体是由数十亿个细胞组成的，但我们从一个受精卵开始分裂成两个，然后四个，然后八个细胞等，一旦这些细胞成为一个功能有机体，许多细胞继续分裂，并帮助再生受损组织。有时细胞分裂出错，细胞无法控制地分裂，产生癌性肿瘤。我们试图了解细胞如何设法避免这种情况。为了使细胞正确分裂，它们必须复制它们的DNA，然后将每个副本分离到细胞的相对两侧，这样当细胞分裂为两个时，每个新细胞继承一个DNA副本。复制的DNA被称为微管的分子“纤维”拉开，这些纤维由称为中心体的球形物体形成。纤维从位于DNA两侧的两个中心体之一伸出，然后附着并将复制的DNA拉开。重要的是，每个子细胞只继承一个中心体，但需要两个中心体才能再次分裂。因此，中心体必须自我复制，并且这个复制过程不能出错，因为当细胞试图分离复制的DNA时，产生太多的中心体会导致问题，这可能导致癌症。我们的主要目标是了解中心体复制是如何被正确控制的。中心体是由一对圆柱形的结构组成，称为中心粒。在中心体复制过程中，这些中心粒分裂产生两个新的中心体。为了确保这种情况在接下来的细胞周期中发生，每个中心粒必须产生一个新的“女儿”中心粒，从而在每个中心粒中产生一对新的母子中心粒。虽然在正常情况下，在这个过程中只会产生一个新的子中心粒，但在一个母中心粒上可能会形成多个子中心粒，这最终会导致产生太多的中心粒。在细胞内，中心体与包围DNA的膜紧密相连，称为核被膜。出乎意料的是，我们最近发现，女儿中心粒倾向于形成在一侧的母亲中心粒面对核膜，当我们人工分离的中心体从核膜的位置女儿中心粒组装在母亲是随机的。我们想研究是否母亲中心粒和核膜之间的局部环境驱动子中心粒组装。我们预测，这可能有助于确保在每个中心粒复制事件中只有一个新的子体组装。我们将使用果蝇作为模型系统来测试这一点，因为我们可以很容易地操纵它们的基因组，为我们的实验创造理想的条件。果蝇的大多数基因与我们的相似，中心粒复制的过程在果蝇和人类中非常相似。因此，我们在苍蝇中的发现对于了解人类健康和疾病非常重要。我们还与一个研究人类细胞系的实验室建立了合作关系，我们将利用从果蝇身上学到的信息来研究细胞结构（如核膜）如何影响和帮助控制人类细胞中的中心粒复制。