Bacterial genes to function: Determining the roles of the gut microbiome in preterm infant health and disease

发挥功能的细菌基因：确定肠道微生物组在早产儿健康和疾病中的作用

• 批准号: 2751202
• 金额: --
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2751202
• 关键词: Bacterial; genes; function; Determining; roles

Preterm infants born <32 weeks gestation are 'immature' physiologically, anatomically and immunologically. Around 10% will develop necrotising enterocolitis (NEC), a deadly inflammatory mediated bowel disease. Abnormal gut microbiome development is integral to NEC pathogenesis. Metagenomic and 16S amplicon sequencing approaches have shown that NEC infants have reduced gut microbial diversity, increased Proteobacteria (gram-negative), and reduced Bifidobacterium (gram-positive). However, these approaches alone do not allow for the functional roles of bacterial species within the microbiome to be characterised. In depth study of these functions and how different species interact is critical to understanding the microbe-microbe and microbe-host interactions that drive and maintain changes in the gut microbiota of NEC or healthy infants.The project will be based on preterm infant health and disease, but there is flexibility in what the student can focus on, which can be modified as the project progresses. Some key objectives are likely to include:1) Determine the metabolic functional capacities of bacterial strains isolated from both healthy and NEC infants2) Investigate metabolic cross-feeding between bacterial strains and determine competition or synergism3) Experimentally test the function of bacterial strain interactions within the host intestinal epithelium using a powerful ex vivo preterm organoid co-culture modelThe student will work closely with academic and clinical supervisors and will have access to the Great North Neonatal Biobank, the largest biobank of preterm samples anywhere in the world. From this resource we have already isolated ~250 novel bacterial and fungal isolates (currently undergoing whole genome sequencing). Our group have also established a novel method for generating preterm organoids and performing co-culture of anaerobic bacteria and preterm epithelium. This PhD studentship will advance our existing research portfolio and build on the tools and extensive data we have already generated. This promises to give a deep understanding of preterm health and disease with potential for developing new biomarkers and therapeutics.The clinically focused work incorporates both discovery and translational aspects. During the course of this interdisciplinary project, the student will gain a wide range of relevant experience in wet-lab techniques including microbiology, molecular biology, biochemistry, tissue culture, transcriptomics (host), metatranscriptomics (bacteria), alongside computational skills including the bioinformatic and statistical analysis of large multi-omic datasets. Such skills are highly-transferable.We are a diverse, fun, and inclusive research group, with positive research culture at the heart of our ethos. We encourage applications from under-represented groups and first-generation students.

小于32周出生的早产儿在生理、解剖和免疫上都是不成熟的。大约10%的人会患上坏死性小肠结肠炎（NEC），这是一种致命的炎症介导的肠道疾病。异常的肠道微生物组发育是NEC发病机制的组成部分。宏基因组和16 S扩增子测序方法表明，NEC婴儿肠道微生物多样性减少，变形菌（革兰氏阴性）增加，双歧杆菌（革兰氏阳性）减少。然而，这些方法本身并不允许表征微生物组内细菌物种的功能作用。深入研究这些功能以及不同物种如何相互作用，对于理解微生物-微生物和微生物-宿主相互作用至关重要，这些相互作用驱动和维持NEC或健康婴儿肠道微生物群的变化。该项目将基于早产儿健康和疾病，但学生可以专注于什么，这可以随着项目的进展而修改。一些关键目标可能包括：1）确定从健康和NEC婴儿中分离的细菌菌株的代谢功能能力2）研究细菌菌株之间的代谢交叉喂养并确定竞争或协同作用3）使用强大的体外早产类器官共培养模型实验性测试宿主肠上皮内细菌菌株相互作用的功能学生将与学术和临床主管密切合作，并将获得Great North Neonatal Biobank，这是世界上最大的早产样本生物库。从这个资源中，我们已经分离出约250种新型细菌和真菌分离株（目前正在进行全基因组测序）。我们的小组还建立了一种新的方法来产生早产儿类器官，并进行厌氧菌和早产儿上皮的共培养。这项博士生奖学金将推进我们现有的研究组合，并在我们已经生成的工具和大量数据的基础上再接再厉。这有望使人们对早产儿健康和疾病有深入的了解，并有可能开发新的生物标志物和治疗方法。临床重点工作包括发现和转化两个方面。在这个跨学科项目的过程中，学生将获得广泛的湿实验室技术相关经验，包括微生物学，分子生物学，生物化学，组织培养，转录组学（主机），元转录组学（细菌），以及计算技能，包括大型多组数据集的生物信息学和统计分析。我们是一个多元化、有趣和包容的研究团队，积极的研究文化是我们精神的核心。我们鼓励来自代表性不足的群体和第一代学生的申请。