Molecular mechanisms of kinesin-5s in fungal mitosis

这项研究的目的是发现细胞复制是如何控制的，以及它可能如何被阻止。我们将重点研究真菌中的细胞复制，这既是因为它们是研究复制的优秀和成熟的模式生物，也因为真菌疾病在医学、环境和经济上具有重要意义。特别是，我们想要研究一种真菌的细胞复制机制，这种真菌感染玉米并导致玉米黑粉病。这种作物病害对全球粮食安全构成重大威胁，特别是因为出现了对现有杀菌剂的抗药性。通过了解玉米黑粉菌是如何复制的，我们希望首先对细胞复制的机制提供一般性的见解。其次，我们希望揭示真菌特有的细胞复制的独特特征，因为这一知识有望帮助开发新的杀菌剂。就像我们的身体有一个为我们提供支持和力量的骨架一样，真菌细胞有一个骨架--称为细胞骨架--它也提供支撑和结构。细胞骨架参与真菌生命的许多重要方面，包括细胞运输、结构和复制。研究细胞骨架很重要，这样我们就可以了解健康细胞是如何工作的，也可以用药物专门针对病原体的细胞骨架，杀死这些生物并预防疾病。特别是，这个项目将专注于细胞骨架的一部分，称为微管。这些是长长的圆柱形结构，就像分子运输马达携带细胞货物的轨道一样。我们将研究的马达被称为运动蛋白，有许多不同的类型。在这个项目中，我们将研究一种激动素-5，它对准确的细胞复制很重要。我们想知道真菌Kinesin-5在复制过程中如何使用细胞燃料沿微管移动，以及这种活动可能如何被阻止。伯克贝克研究小组的工作将涉及研究细胞骨架的三维结构，因为了解细胞骨架的样子将有助于我们理解它在真菌本身中是如何工作的。我们将使用一种非常强大的显微镜-电子显微镜-来拍摄单个细胞骨架分子的照片，然后使用计算分析将这些图像组合在一起，计算出它们的三维形状。拟议项目的一个强有力的方面是，我们还将与埃克塞特大学的真菌细胞生物学专家合作，研究Kinesin-5在活的玉米黑粉菌中的功能。与许多其他真菌不同，玉米黑粉菌的细胞相对较大(10微米)。这意味着可以使用光学显微镜详细研究单个细胞的细胞复制，以便我们的合作者能够可视化活着的真菌中Kinesin-5s的活性，并检查阻止其活性对真菌生存的影响。初步分析表明，来自真菌的Kinesin-5s不同于来自包括人类在内的其他生物体的kinesin-5s。这意味着我们可能能够找到能够阻止真菌激动素-5而不是人类激动素-5的药物，而且这种药物作为新的杀菌剂可能非常有希望。研究真菌Kinesin-5的结构和功能将使我们能够研究这一想法。

The purpose of this research is to discover how cell replication is controlled and how it might be blocked. We will focus our studies on cell replication in fungi, both because they are excellent and well-established model organisms for studying replication, and because fungal diseases are medically, environmentally and economically important. In particular, we want to investigate the cell replication machinery in a fungus that infects corn and causes the disease corn smut. This crop disease poses a major threat to global food security, particularly because of the emergence of resistance to currently available fungicides. By understanding how the corn smut fungus replicates, we hope to first, provide general insight into the mechanisms of cell replication. Secondly, we hope to uncover unique features of fungus-specific cell replication because this knowledge promises to help in the development of novel fungicides.In the same way as our bodies have a skeleton that provides us with support and strength, the cells of fungi have a skeleton - called the cytoskeleton - which also provides support and structure. The cytoskeleton is involved in many important aspects of the life of fungi, including cellular transport, architecture and replication. Studying the cytoskeleton is important both so we can understand how healthy cells work, but also so we can specifically target the cytoskeleton of pathogenic organisms with drugs that kill these organisms and prevent disease.In particular, this project will focus on a part of the cytoskeleton called microtubules. These are long cylindrical structures that act like tracks along which molecular transport motors carry cellular cargo. The motors that we will study are called kinesins and there are many different types. In this project, we will be studying a kinesin type-5, which is important for accurate cell replication. We want to know how fungal kinesin-5s use cellular fuel to move along microtubules during replication and how this activity might be blocked. The work by the Birkbeck research team will involve studying the three-dimensional structure of the cytoskeleton, because knowing what the cytoskeleton looks like will contribute to our understanding of how it works in the fungus itself. We will use a very powerful microscope - an electron microscope - to take pictures of individual cytoskeleton molecules and then use computational analysis to combine these pictures and calculate their three-dimensional shape. A powerful aspect of the proposed project is that we will also study the function of kinesin-5 in live corn smut fungus, in collaboration with experts in fungal cell biology at the University of Exeter. Unlike many other fungi, which are very small, the cells of the corn smut fungus are relatively large (10um). This means that cell replication of individual cells can be studied in detail using light microscopy, so that our collaborators will be able to visualise the activity of kinesin-5s in the living fungus and examine the effects of blocking its activity on fungal survival.Initial analysis suggests that the kinesin-5s from fungi are different from kinesin-5s from other organisms, including humans. This means that we might be able to find drugs that can block fungal kinesin-5 and not human kinesin-5, and such drugs could be very promising for development as new fungicides. Studying the structure and function of the fungal kinesin-5s will allow us to investigate this idea.