The glycocalyx is a protective gel-like layer that lines the endothelial cells of all blood vessels. Glomeruli are the microvessels in the kidney that filter blood (retaining larger proteins, such as albumin) and are lined with glycocalyx.1 Glomerular glycocalyx damage is associated with low-level albuminuria (progressing to more severe albuminuria) found in individuals with type 1 & 2 diabetes who are also known to have reduced systemic glycocalyx volume. 2,3 Albuminuria and reduced glomerular filtration rates (GFR) are indicators of kidney disease. The importance of glycocalyx in kidney function has not yet been validated in large population datasets, which is necessary to support development of clinical targets.
For the first 6 months of the PhD, the student will train in different areas of data analysis across various existing projects within Bristol Renal. This will include familiarisation with projects in both genetic epidemiology and bioinformatics for analysis of ‘omics’ data sets. Training will be provided by supervisors, collaborators and through short courses run by UoB, such as Introduction to Linear and Logistic Regression Models (5-day course); Introduction to Data Visualisation and Web Applications Using R (2-day course); Genetic Epidemiology (5-day course); Molecular Epidemiology (3-day course); Mendelian Randomization (4-day course).
There will also be opportunity for experience and training in some wet lab techniques such as endothelial cell culture and glycocalyx assays after exposing cells to disease conditions and drugs.
During the first six months a more focused project for the remainder of the PhD will be developed under the main themes of genetic epidemiology or bioinformatics. Some specific examples are as follows:
Aims
The project aims to use large population datasets to validate the importance of the glomerular endothelial glycocalyx in kidney function.
Methods
Option 1: Genetic epidemiology using UK Biobank datasets
Shrunken pore syndrome kidney disease is characterised by reduced filtration of medium sized proteins (such as cystatin C) by the glomerulus, yet normal filtration of smaller proteins (such as creatinine).
We have performed the largest epidemiological study of shrunken pore syndrome to date using UK Biobank data (500,000+ patients) which confirms that a lower ratio of clearance of cystatin C to creatinine is associated with multiple social and health-related characteristics. We have also identified common genetic variants (>40,000) that are associated with the ratio of cystatin C and creatinine clearance in a genome-wide association study.
We will interrogate the results of the GWAS to determine whether any of the genetic variants are within known glycocalyx genes or affect the expression of glycocalyx components (expression quantitative loci) using the Genotype-Tissue Expression database. We will then use Mendelian randomisation to investigate evidence for a causal relationship between glycocalyx-associated gene expression, and an altered ratio of cystatin C and creatinine.
Option 2: Bioinformatics work with existing datasets
Single cell RNA sequencing will be analysed from endothelial cells isolated from rodent glomeruli of wild type and kidney disease models (e.g sepsis AKI, diabetes), including animals or glomeruli treated with drugs known to be effective in DKD/CKD or being developed for this therapeutic application. Single nuclear RNA sequencing will also be analysed from rodent glomerular endothelial cells from kidney disease models.
Endothelial glycocalyx associated changes in health and kidney disease will be explored and compared to endothelial cell signatures from single nuclear RNA sequencing of human kidney biopsies from patients with a range of kidney diseases (Cardiff).
Option 3: Avon longitudinal study of children of the 90’s (ALSPAC) glycocalyx GWAS
Glycocalyx measures in patients or the general population are very limited, which restricts meaningful research and therapeutic development. Indirect measures of systemic glycocalyx depth (termed perfused boundary region) have been taken in the ALSPAC cohort (http://www.bristol.ac.uk/alspac/researchers/our-data/) using sidestream dark field imaging, in conjunction with Glycocheck software analysis. We have cleaned these data, which now present the potential for investigating genome-wide associated changes with perfused boundary region measures, creating a glycocalyx-related GWAS, for the first time. This analysis can be performed as part of the PhD. In addition, any independent genetic variants identified in the GWAS can be used in Mendelian randomisation analyses to investigate causal relationships between the glycocalyx measures and disease.
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 1100 members of staff, 1350 undergraduate, 250 postgraduate taught and 300 postgraduate doctoral research students. The Head of School is Professor Chrissie Thirlwell. The Medical School has two departments: Population Health Sciences and Translational Health Sciences. The School is a leading centre for research and teaching across these areas. Research in the School is collaborative and multi-disciplinary, with staff coming from a wide range of academic disciplines and clinical specialties.
This post will be based in the Dorothy Hodgkin Building.
How to apply for this project
This project will be based in Bristol Medical School – Translational Health Sciences in the Faculty of Health and Life Sciences at the University of Bristol. Use this information to search for the relevant programme in our online application system. Applicants should include the names of two supervisors (with their agreement after discussion of the research proposal). This project does not come with funding. If you have secured your own sponsorship or can self-fund this PhD please visit our information page here for further information on the department of Translational Health Science and how to apply.