Additional supervisor: Prof Patrick Mark [University of Glasgow]
Background
Chronic kidney disease (CKD) is a major public health problem, affecting ~11% of the UK population and conferring an increased risk of cardiovascular disease and end-stage kidney disease (ESRD), which necessitates dialysis or transplantation1. Hence, novel therapies are required to prevent progression of CKD or promote kidney repair. Furthermore, we need to determine which therapies work best for specific kidney diseases or stages of disease progression.
The kidney is a complex organ, comprised of multiple cell types, therefore to identify the molecular pathways that are activated/deactivated in each cell type we are employing state-of-the-art single-cell multimodal molecular techniques. As part of a previous Precision Medicine PhD studentship, we employed single-nuclear RNA/ATAC-seq on tissue from the non-tumerous portion of human kidneys removed due to tumour, including a subset of patients where the tumour obstructed the ureter causing kidney injury, inflammation and scarring3. We identified a discrete subset of tubular cells that adopts a pro-inflammatory phenotype and employed high-plex spatial single-cell molecular analysis to localize pro-inflammatory tubular cells to the fibrotic niche. Importantly, we identified the AP-1 transcription factor as a key master regulator of the inflammatory tubular cell phenotype and administration of an AP-1 inhibitor ameliorated inflammation and fibrosis in a murine model of kidney disease. This provides proof-of-principle that single-cell, multi-omic interrogation of kidney tissue can identify novel therapies to treat kidney disease.
To identify disease-specific pathways of renal injury, we are currently performing snRNA-seq on archived frozen kidney biopsy cores from patients with a diverse range of kidney diseases. Uniquely, we have access to biopsies from patients with vasculitis, both before and after immunosuppressive treatment, enabling discrimination between mechanisms of injury and repair. Our preliminary analysis has identified tubular cell, inflammatory and fibroblast subsets that are disease-specific or present specifically during disease progression or repair. This raises the exciting possibility that we can develop disease-specific therapies to slow progression of kidney disease or indeed enhance kidney repair. This is vitally important, as kidney disease is often silent until the late stages, meaning patients often present with advanced disease.
Aims
The current project will aim to interrogate our existing snRNA-seq datasets to identify cellular mechanisms of kidney disease, develop tools to identify pathogenic/reparative cells in human kidney biopsies and screen drugs to inhibit development of pathogenic cell types. Specific aims for the project are to:
Training outcomes
The student will work with clinicians, experimental biologists and bioinformaticians to address key research questions in kidney disease. They will gain generic and transferable skills including: handling of large datasets in the R environment, visualization of complex snRNA-seq and spatial transcriptomic data, statistics, presenting data to peers, writing of manuscripts, etc. They will be trained in development of multiplex immunofluorescence antibody panels for imaging kidney tissue on Phenoimager and data analysis in QPath. In addition, they will learn renal cell biology, and be trained in core wet bench skills including tissue culture, viral transfection and generation of reporter assays.
Q&A Session
If you have any questions regarding this project, you are invited to attend a Q&A session hosted by the Supervisor(s) on Wednesday 10th December at 1pm GMT via Microsoft Teams. Click here to join the meeting.
About the Programme
This MRC programme is a joint programme delivered between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection and will be awarded upon successful completion of your PhD will be awarded by your lead institution.
All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with the University of Glasgow. Please note, you must apply to a specific project as advertised on the Precision Medicine webpages and FindAPhD. Additional information on the application process is available at the link below:
https://www.ed.ac.uk/usher/precision-medicine/app-process-eligibility-criteria
For more information about Precision Medicine visit: