The role of diacylglycerol delta, DGKD, and WD repeat-containing protein 72, WDR72, in renal dysfunction and kidney stone disease
Dr Sarah Howles, Nuffield Department of Surgery, and Professor Antony Galione, Department of Pharmacology
About this project
Kidney stone disease is a major clinical and economic health burden, affecting ~20% of men and ~10% of women by 70 years of age. The prevalence of kidney stone disease is rising, up to 50% of individuals who have formed a kidney stone will experience a second stone episode within 10 years of presentation, and renal stones are linked to chronic kidney disease. The homeostatic and renal tubular mechanisms underlying these disease processes are poorly understood, current stone prevention strategies are relatively ineffective, and the need for improved treatments is widely recognised.
We used large-scale genomic studies in combination with single cell ATAC-sequencing data from human kidneys to identify factors that commonly increase risk of kidney stone disease. Our findings indicate that alterations in renal tubular endocytosis, beta intercalated cell (ICB) activity, and calcium-sensing receptor signalling have a role in kidney stone disease and renal dysfunction due to alterations in diacylglycerol kinase delta and WD repeat-containing protein 72 expression and structure. We will use laboratory methods to study these pathways in vitro, characterising the effects of disease-associated missense variants and using CRISPR-Cas9 to investigate effects of predicted causal non-coding variants. We will use genetically modified human renal organoids to identify additional cellular pathways of interest for study via scRNAseq analysis and use histological techniques to identify alterations in tubular morphology and protein expression. We will study the effects of pharmacological agents in rectifying perturbed cellular function in vitro to identify potential novel therapies for kidney stone disease and renal failure.
We combine molecular biology techniques (including studies of fluid-phase and receptor-mediated endocytosis, characterisation of intracellular signalling pathways, and immunohistochemistry), cellular genetics (including CRISPR-Cas9 genome editing), studies of cellular models of disease (including renal organoids), and transcriptomics (including scRNA-seq and associated bioinformatic analyses) to provide comprehensive investigation of and training in studies of renal physiology and disease. Weekly laboratory meetings will provide training in presentation of data in anticipation that students will participate in national and international conferences and students will attend scientific training courses including scientific writing and statistical analysis.