Lipid remodelling in host-pathogen interaction and antimicrobial resistance

项目概述：这个由MRC资助的博士培训伙伴关系（DTP）将尖端的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，使学生能够解决以假设为主导的生物医学研究问题。这是一个为期4年的计划，其第一年涉及一系列教学模块和两个基于实验室的研究项目，导致跨学科生物医学研究硕士学位。前两个学期包括一系列教学模块，让学生在多学科科学中获得坚实的基础。学生还参加了一系列由学术和行业专家领导的大师班，这些专家在分子，细胞和组织动力学，微生物学和感染，应用生物医学技术以及人工智能和数据科学领域。在第三和夏季学期，学生在他们选择的实验室进行两个为期11周的研究项目。项目：抗菌药物耐药性（AMR）描述了微生物否定用于治疗它们的药物的作用的能力。这包括细菌对抗生素的耐药性，其中个别细菌物种对多种不同类别的抗生素产生耐药性。一种这样的多药耐药物种是铜绿假单胞菌（P. aeruginosa）;一种通常伴随其他现有疾病出现的细菌物种，例如在囊性纤维化或烧伤患者中。铜绿假单胞菌由于其对抗生素的天然低敏感性而特别成问题，而其他细菌物种需要获得它们的抗生素抗性机制。细菌细胞有一个由脂质（脂肪）组成的外膜，这是它们抵抗抗生素攻击的第一道屏障。细胞膜通常含有抗性机制，如将药物泵出细胞或将其分解的蛋白质。重要的是，细菌还具有改变构成外膜的脂质类型的能力。这导致膜的渗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和膜脂质组成变化之间的联系。为了研究该假设，首先将证实铜绿假单胞菌能够响应于临床相关环境而改变其膜中的脂质。随后，在细菌修饰其脂质膜后，将测试各种不同类别的抗菌剂，看看这是否会改变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蠕虫（线虫），秀丽隐杆线虫和实验室培养的人类细胞，研究细菌膜脂质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.