Inflammation attacks the kidney’s microscopic blood filters, and this project will map exactly which cells sound the alarm and how. Glomerulonephritis—a family of inflammatory kidney diseases—is a leading cause of kidney failure worldwide, yet doctors lack targeted treatments because the earliest molecular steps remain poorly understood. The researcher will take healthy human kidney cells, expose them to inflammatory signals, and use single-cell RNA sequencing to track which genes each cell type switches on. They will then test whether blood serum from patients with active glomerulonephritis triggers the same patterns, building a computational model of how inflammation spreads through the filter. If successful, this fundamental science will create a detailed atlas of the kidney’s inflammatory response—a resource that could eventually guide the design of drugs that block the very first steps of damage, rather than treating symptoms after the kidney is already scarred. It may also lead to diagnostic tests that distinguish between different forms of glomerulonephritis based on their molecular signatures, enabling earlier and more precise treatment.
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Glomerulonephritis (GN) is a leading cause of kidney failure, and is characterised by inflammation and damage to the glomerular filtration apparatus. Collectively GNs represent a leading cause of end stage kidney disease. A detailed molecular understanding of the roles of the parenchymal cells (endothelial cells, mesangial cells, and podocytes) in the earliest steps of pathogenesis and how this varies between inflammatory kidney diseases is lacking. Our previous work has highlighted monocyte-derived IL1 and TNF signalling to the glomerular endothelium as a key mechanism orchestrating glomerular inflammation in response to IgG immune complexes. In this project I aim to define the cell-type specific gene expression signatures induced by candidate cytokines. Using high-throughput scRNAseq with metabolic labelling of nascent transcripts, I will profile cells from healthy human glomeruli following cytokine stimulation. I will use the resulting data to define a response cell state map, and to generate a mechanistically-informed computational model of inflammatory signalling in the glomerulus. Equipped with this atlas-scale data, I plan to use multiplexed bulk RNAseq profiling to assay the transcriptional responses of healthy glomeruli to sera from patients with active glomerular inflammation (rapidly progressive IgA nephropathy, class IV lupus nephritis, and ANCA vasculitis), computationally decoding the signalling dynamics shaping the establishment of glomerular inflammation. This molecular systems immunology approach to glomerular disease will lay the foundation for further larger scale studies aimed at rational therapeutic target identification, and the development of next-generation diagnostic approaches.
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