Lipid remodelling in host-pathogen interaction and antimicrobial resistance

课程概述：这个由MRC资助的博士培训伙伴关系(DTP)将尖端分子和分析科学与数据分析中的创新计算方法结合在一起，使学生能够解决假设引导的生物医学研究问题。这是一个为期4年的课程，第一年包括一系列的教学模块和两个基于实验室的研究项目，这些项目导致了跨学科生物医学研究的硕士学位。前两个学期包括精选的教学模块，使学生能够在多学科的科学中获得坚实的基础。学生们还参加了由学术和行业专家主持的一系列大师课程，这些专家涉及分子、细胞和组织动力学、微生物学和传染病、应用生物医学技术以及人工智能和数据科学等领域。在第三学期和暑期，学生们在他们选择的实验室里进行两个为期十一周的研究项目。项目：抗菌素耐药性(AMR)描述了微生物抵消用于治疗它们的药物的效果的能力。这包括细菌对抗生素的抗药性，在这种情况下，单个细菌物种对多种不同类别的抗生素产生抗药性。具有多重耐药性的铜绿假单胞菌就是其中之一；这是一种经常与其他现有疾病同时出现的细菌，例如囊性纤维化或烧伤患者。铜绿假单胞菌的问题尤其严重，因为它对抗生素的自然敏感性很低，而其他细菌物种需要获得它们的抗生素耐药性机制。细菌细胞有一个由脂质(脂肪)组成的外膜，这是它们抵御抗生素攻击的第一个屏障。这种膜通常含有耐药机制，例如将药物泵出细胞的蛋白质，或将其分解的蛋白质。重要的是，细菌也有能力改变组成外膜的脂质类型。这会导致膜的通透性和选择性发生变化，可能会影响药物进入细菌细胞的能力。该项目的目的是建立抗菌素耐药性与膜脂成分变化之间的联系。为了研究这一假说，首先将确认铜绿假单胞菌能够改变其膜上的脂质以响应临床相关环境。随后，在细菌修饰其脂膜后，将对各种不同类别的抗菌剂进行测试，看看这是否改变了它们杀死细菌的能力。最后，该项目将通过使用科学研究中经常使用的一种蠕虫(线虫)--秀丽线虫--以及实验室培养的人类细胞，研究细菌膜脂的变化如何影响其与目标宿主相互作用的能力。

Programme overview:This MRC-funded doctoral training partnership (DTP) brings together cutting-edge molecular and analytical sciences with innovative computational approaches in data analysis to enable students to address hypothesis-led biomedical research questions. This is a 4-year programme whose first year involves a series of taught modules and two laboratory-based research projects that lead to an MSc in Interdisciplinary Biomedical Research. The first two terms consist of a selection of taught modules that allow students to gain a solid grounding in multidisciplinary science. Students also attend a series of masterclasses led by academic and industry experts in areas of molecular, cellular and tissue dynamics, microbiology and infection, applied biomedical technologies and artificial intelligence and data science. During the third and summer terms students conduct two eleven-week research projects in labs of their choice. Project:Antimicrobial resistance (AMR) describes the ability of microbes to negate the effects of the drugs used to treat them. This includes the resistance of bacteria to antibiotics, within which individual bacterial species are becoming resistant to multiple different classes of antibiotics. One such multi-drug resistant species is Pseudomonas aeruginosa (P. aeruginosa); a bacterial species that often presents concomitantly with other existing illnesses, for example in cystic fibrosis or burns patients. P. aeruginosa is particularly problematic due to its naturally low susceptibility to antibiotics, whereas other bacterial species need to acquire their mechanisms for antibiotic resistance. Bacterial cells have an outer membrane, composed of lipids (fats), that is their first barrier to antibiotic attack. The membrane often contains resistance mechanisms, such as proteins to pump the drug back out of the cell, or to break it down. Importantly, bacteria also have the ability to change the types of lipids that make up the outer membrane. This results in changes to the permeability and selectivity of the membrane, with the possibility that this affects the ability of the drug to enter the bacterial cell. The aim of this project is to establish the link between antimicrobial resistance and the changes in membrane lipid composition. To investigate this hypothesis, first it will be confirmed that P. aeruginosa is able to modify the lipids in its membrane in response to clinically relevant environments. Subsequently, various different classes of antimicrobials will be tested after the bacteria has modified its lipid membrane, to see if this alters their ability to kill the bacterium. Finally, the project will investigate how the changes to the bacterial membrane lipids affect its ability to interact with the target host, through using both a species of worm (nematode) frequently used in scientific research, Caenorhabditis elegans, and also laboratory cultured human cells.