This is an exciting opportunity to undertake a funded PhD in a novel area of kidney research, investigating the causal role played by the gut microbiome in diabetic kidney disease. This project will allow the appointed student to develop skills in molecular and genetic epidemiology alongside fundamental laboratory sciences.
Background
Diabetic kidney disease (DKD) is a major cause of kidney failure worldwide and occurs in up to 50% of diabetic individuals. With the increasing incidence of DKD and limited treatment options, there is a need to identify novel therapeutic targets and biomarkers of DKD incidence and progression.
There has been a growth in research sparking interest in the utility of the gut microbiome – a complex system of microorganisms – in the diagnosis, prevention and treatment of human diseases, including type 2 diabetes and DKD. However, the role of the microbiome in DKD in humans is still relatively unexplored and existing population studies have a limited ability to draw causal inference.
Initial genome-wide association studies (GWASs) have enabled the appropriate application Mendelian randomization (MR) to assess the impact of the microbiome on various outcomes, through the careful examination and interpretation of derived causal effects.
This project will combine human genetics with population health research, alongside studies using human kidney cells in the laboratory to help understand if there is a causal relationship between changes in the gut microbiome and DKD.
Overall Aim of the PhD
The overarching hypothesis of this project is that variation in the gut microbiome has a causal role in DKD incidence and progression.
Objectives
The projects primary objectives are:
- Apply contemporary causal methods to investigate the role of the gut microbiome in DKD aetiology;
- Examine the likely impact of reverse causation in the relationships between the gut microbiome and DKD incidence and progression;
- Use complementary laboratory studies on kidney cell models to investigate the causal mechanisms linking the gut microbiome and DKD;
- Assess the association between genome-wide predictors of the gut microbiome and DKD risk and progression outside causal framework analyses.
Methodology
Epidemiological findings (objectives 1 and 2) will identify possible causal effects of the gut microbiome on DKD aetiology to be further interrogated in the laboratory (objective 3), where the direct effects of the altered microbiome and microbiota-derived metabolites on kidney cell function will be explored. Analyses conducted for objective 4 will examine whether the gut microbiome is a marker of DKD (rather than a cause) and could therefore be used to identify those at risk of developing the disease.
Epidemiological methods will include traditional epidemiological and MR analyses in large-scale population data to evaluate the causal role of the gut microbiome in DKD aetiology. The student will acquire a direct understanding of the nature of the host genetic contributions to host microbiome variation but also an appreciation of the likely complexities when using genetic associations in epidemiological frameworks assessing causality. For objective 4, the student will use polygenic risk scores capturing genome-wide genetic variation rather than those reaching a genome-wide significance threshold. The student will assess whether inherited susceptibility to gut microbiome variation is associated with the development or progression of DKD and related intermediates (e.g., albuminuria).
Epidemiologically-informed laboratory experiments will include high-throughput microscopy assays on conditionally-immortalised human cell lines to screen changes in biologically relevant pathways (e.g., apoptosis, metabolic pathways and inflammation).
University of Bristol, Bristol Medical School
Bristol Medical School is the largest and one of the most diverse Schools in the University of Bristol, with approximately 930 members of staff and over 300 postgraduate doctoral research students. The School is a leading centre for research and teaching across Population Health Sciences and Translational Health Sciences. Research in the School is collaborative and multi-disciplinary, with staff coming from a wide range of academic disciplines and clinical specialties.
The 2014 Research Excellence Framework (REF) confirmed the University of Bristol’s position as a leading centre for health research. In Population Health Sciences 50% of our research was rated as 4* (world leading), and 86% as 4* or 3* (world- leading or internationally excellent). 100% of our research impact case studies were rated as world-leading, as was 100% of our research environment. This recognition of our outstanding impact and research environment reflects our engagement with patients, the public and policy makers and our commitment to training, staff development, multi-disciplinary research and collaboration. In the areas of Clinical Medicine and Psychology, Psychiatry and Neuroscience returns from staff in the Medical School also had approximately 80% in the world-leading (4*) or internationally excellent (3*) categories.
Within the Medical School are several major research centres, groups and programmes. More details can be found on the Medical School website.
How to apply
Apply online. Select “Population Health Sciences” PhD programme and state in the application that you are applying for funding from Kidney Research UK. Please ensure you have read our admissions statement before making an application. We request a 2 page research proposal from you as part of the application. This should be in your own words and an outline of the project as you understand it.
Applicants should hold (or be about to obtain) at least an upper second class honors degree or Masters degree (or equivalent) in biological sciences or a related discipline, with an interest in the gut microbiome and kidney research. Candidates who have previous laboratory or bioinformatic research experience are particularly encouraged to apply. Pre-application enquires are encouraged.
Shortlisted applicants will be invited for interview in June 2022.
Enquiries: Dr Kaitlin Wade [Email Address Removed] and Dr Abigail Lay [Email Address Removed]
Closing Date: 27th May 2022
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