Integration of single-cell RNA sequencing data from human and murine kidney disease to identify novel therapeutic targets

Chronic kidney disease (CKD) is a major risk factor for cardiovascular disease and for end-stage kidney disease (ESRD), at which point patients require dialysis or transplantation. CKD affects 7% of the UK population and therefore constitutes a major public health problem. Despite the best current management, a minority of patients with CKD progress to ESRD, hence novel therapies are required to prevent progression of CKD or promote regeneration of the injured kidney.
To identify novel therapeutic targets, we are conducting studies to identify molecular pathways that are differentially activated in the kidney in patients with CKD compared with healthy controls. We are also employing a number of animal models of kidney disease including diabetic nephropathy, unilateral ureteric obstruction (UUO), ischaemia-reperfusion injury (IRI) and subtotal nephrectomy. Importantly, we have adapted the diabetic nephropathy, UUO and IRI models to investigate mechanisms of renal repair after injury; this cannot be easily monitored in human disease as kidney biopsies are rarely performed in patients who are improving clinically. Our research focuses on understanding which pathways are activated in our animal models during injury and repair in particular inflammation and senescence. We anticipate that this may highlight novel therapeutic targets to inhibit progression of disease or promote kidney repair.

The overarching plan for the project is to interrogate the scRNA-seq datasets that we have accrued from our murine models of kidney disease to identify pathways and specific cell types that are implicated in disease. These will then be compared with similar studies in human kidney disease to identify translational targets for therapy.

Specific aims include:
1. To integrate the datasets from our murine models in order to identify common and disease-specific pathways of renal injury and repair
2. To perform a detailed analysis of the murine datasets t o further understand the biology, in particular assessing the cell-to-cell signaling pathways that promote inflammation, fibrosis, senescence and regeneration
3. To integrate the snRNAseq data from patients with CKD with the murine datasets to determine which murine model most closely reflects the pathogenesis of specific kidney diseases and hence may be most suitable to employ in future mechanistic/drug development studies
A particular aim is to explore these datasets with a focus on immune cell senescence. Kidney disease is known to induce premature cell senescence, so the goal will be to compare the senescence signature in the kidney injury models with that of the Tabular Muris Senis and with human kidney disease. Ultimately, in vitro and in vivo models will be used to determine whether administration of anti-senescence therapies specifically deplete senescent cells in human kidneys.