Structural characterization of the bacterial flagellum basal body

许多细菌利用其表面的一种叫做鞭毛的长而旋转的细丝在周围环境中游动，并附着在固体表面上。特别是，这些特征对于许多致病菌如大肠杆菌、沙门氏菌、志贺氏菌等都是必不可少的。引起疾病这是因为鞭毛允许它们在宿主体内扩散，并附着在它们的细胞上，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大大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尤其具有挑战性。鞭毛的中心区域，称为“基体”，作为一个锚点，围绕着它形成完整的机器。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，鞭毛围绕着这个平台聚集。本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，来生成鞭毛基体的分子“图谱”。然后，我们将利用这张图来确定它的组成部分是如何组合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。这将是特别有趣的，因为鞭毛在细菌中广泛存在，因此这种治疗可以针对各种细菌的感染。此外，与其他已知的纳米机器相比，基体的分子图谱将为细菌如何能够“进化”出鞭毛等结构提供线索。最后，了解鞭毛如何形成可以用来开发移动药物输送系统，这可以用于广泛的药物治疗，如抗癌治疗或基因治疗。

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.