Project Reference: TRG27-PDN-KR1

Project title: Injury and repair in human nephrogenesis in an organoid model

Project outline

The tube of the human nephron, the filtration unit of the adult kidney, forms during development though a mesenchymal-to-epithelial transition (MET) leading to the starting point of the epithelial tube. We uncovered that PAX8 is both necessary and sufficient in human renal organoids derived from iPSCs to drive the MET (Ng-Blichfeldt et al., 2024), and we have recently identified the regulome downstream of PAX8 during this MET.

Building on these initial data, in this PhD project we now want to explore the following:

  1. The MET programme controlled by PAX8

Our multi-ome and CUT&Run analysis of MET revealed PAX8 as a key control element, initiating a cell adhesion programme crucial for MET.

For confirmed targets, we want to use CRISPRi to assess their role in the MET and follow up the function of any of these targets during renal MET and nephron formation. 

  1. PAX8 as the human switch between mesenchymal and epithelial fate

We want to ultimately exploit the fact that PAX8 appears to be both necessary and sufficient for the MET. We want to therefore assess in detail whether ectopic expression of PAX8 elicits the same downstream programme as the developmental activation, using sequencing and cell biological approaches.

  1. An injury model to assess commonality and divergence amongst developmental versus repair programmes

The dual necessity and sufficiency put PAX8 into a prime position as a tool to promote renal repair. The adult kidney lacks resident stem cells, and developmental pathways might be re-employed for repair. To assess PAX8’s ability to stimulate renal repair we will use an established renal injury models, based on hypoxia or cisplatin treatment, and will assess firstly the transcriptional changes during injury and repair, in in how far repair recapitulates developmental changes. We will then test whether targeted re-expression or elevation of expression of PAX8 could be beneficial in aiding or accelerating the repair process.

Principal Supervisor

Professor Katja Röper

Email address: kr250@cam.ac.uk

Department / Partner Institute: Physiology, Development and Neuroscience (PDN)

Website: https://www.pdn.cam.ac.uk/staff/roper

BBSRC strategic theme

Bioscience for an integrated understanding of health