Dissecting the regulation of nephron progenitor identity, self-renewal and commitment at a single cell level

Chronic kidney disease is characterised by gradual loss of renal function over time with end-stage patients requiring organ transplantation or life-long dialysis. This condition affects approximately 10% of our population and treatment costs the Australian health system in excess of $4 billion annually. An average human kidney contains 1,000,000 filtration units called nephrons that cooperate to clean the blood and regulate fluid homeostasis in the body. Low
nephron number is a major risk factor for chronic kidney disease and is associated with environmental and genetic factors that impair kidney development.

Despite this, we are yet to understand how nephron number is regulated. Nephrons arise from a nephron progenitor (NP) population. The balance of NP self-renewal and differentiation influences final nephron number and is critical for optimal kidney development. In this proposal, we will dissect the regulation of progenitor self-renewal versus commitment by characterising mouse knockout models affecting nephron progenitor regulation using single-cell RNA-seq across time. We will also investigate a novel mechanism that may contribute to progenitor ageing. Finally, we will perform a suite of in vivo lineage tracing
to interrogate the origin and fate of a novel NP-stromal cell population we identified by single cell RNA-Seq. The outcomes of this grant will inform our
understanding of nephron progenitor turnover and lifespan in vivo. Understanding which pathways regulate these processes will open up the prospect of enhancing nephron formation. It will also provide critical information for the ex vivo regulation of nephron progenitor expansion and differentiation for the purposes of regenerative medicine.