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Structural characterization of the bacterial flagellum basal body

细菌鞭毛基体的结构特征

基本信息

批准号：
BB/R009759/1
负责人：
Julien Bergeron
金额：
$ 62.25万
依托单位：
University of Sheffield
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%2FR009759%2F1
关键词：
Structural characterization bacterial flagellum basal

项目摘要

Many bacteria utilize a long, rotating filament on their surface, called the flagellum, to swim in their surrounding environment, and for adherence to solid surfaces. In particular, these features are essential for many pathogenic bacteria such as E.coli, Salmonella, Shigella etc.. to cause disease. This is because the flagellum allows them to spread in the host's body, and to adhere to their cells, as well as to medical devices such as catheters. As a consequence, understanding the bacterial flagellum at the molecular level could have numerous medical implication, and disrupting its rotation and adherence properties would largely reduce infection in a clinical setting. However, the flagellum is a very sophisticated nano-machine, and studying its mechanism of action at the molecular level is particularly challenging. A central region of the flagellum, called the "basal body", serves as an anchoring point around which the complete machinery forms. Despite the importance of this region, we know very little about its molecular details, and about how its constituting components come together to form a stable platform around which the flagellum assembles. The objective of the proposed research is to use advanced biophysics methods, including the most cutting-edge electron microscopy techniques, to generate a molecular "map" of the flagellum basal body. We will then exploit this map to determine how its constituting components come together to form such a sophisticated structure. These results could be exploited to generate new therapies that block the formation or function of the flagellum. This would be of particular interest because the flagellum is widespread amongst bacteria, and therefore such therapy could target infections from a wide range of bacteria. In addition, a molecular map of the basal body will provide clues of how bacteria were able to "evolve" structures such as the flagellum, by comparison to other known nano-machines. Finally, understanding how the flagellum forms could be used to develop motile drug delivery systems, which could be exploited for a wide range of medication such as anticancer treatment or gene therapies.

许多细菌利用其表面上的长而旋转的细丝，称为鞭毛，在周围环境中游泳，并粘附在固体表面上。特别是，这些特征对于许多致病性细菌如大肠杆菌、沙门氏菌、志贺氏菌等是必不可少的。导致疾病这是因为鞭毛允许它们在宿主体内传播，并粘附在宿主细胞以及导管等医疗设备上。因此，在分子水平上理解细菌鞭毛可能具有许多医学意义，并且破坏其旋转和粘附特性将在很大程度上减少临床环境中的感染。然而，鞭毛是一个非常复杂的纳米机器，在分子水平上研究其作用机制特别具有挑战性。鞭毛的中心区域，称为“基体”，作为一个锚定点，周围形成完整的机器。尽管这个区域很重要，但我们对它的分子细节知之甚少，也不知道它的组成成分是如何聚集在一起形成一个稳定的平台，鞭毛就在这个平台周围组装。拟议研究的目的是利用先进的生物物理学方法，包括最先进的电子显微镜技术，绘制鞭毛基体的分子“地图”。然后，我们将利用这张地图来确定它的组成部分是如何聚集在一起形成如此复杂的结构的。这些结果可以用来产生新的疗法，阻止鞭毛的形成或功能。这将是特别令人感兴趣的，因为鞭毛在细菌中广泛存在，因此这种疗法可以靶向来自广泛细菌的感染。此外，通过与其他已知的纳米机器进行比较，基体的分子图将提供细菌如何“进化”鞭毛等结构的线索。最后，了解鞭毛形式如何用于开发能动的药物递送系统，这可以用于广泛的药物治疗，如抗癌治疗或基因治疗。