TNDModelling

Transient neonatal diabetes mellitus – TNDM – is a rare genetic disorder that affects approximately one in 200.000 live births. It results from defective pancreatic ß-cell development and/or function. TNDM involves the over-expression of ZAC1, a paternally expressed, maternally imprinted gene on 6q24 in 75% of the cases. To model TNDM, we generated TNDM-like human induced pluripotent stem cells (hiPSCs) by mimicking the epimutation at ZAC1 maternal promoter observed in some patients. We differentiated hiPSCs into pancreatic progenitors (PPs) and identified deregulated genes and biological processes by systems-level approaches. We showed a specification defect in TNDM-like PPs. We also generated ß cells, will characterize their function – insulin content, glucose-stimulated insulin secretion, calcium dynamics, and glucose metabolism – and will identify deregulated biological processes. To test the effect of ZAC1 bi-allelic expression in more mature ß cells, we will transduce human pancreatic islets with the same demethylation system used previously and we will perform functional characterization. We will use the cellular TNDM model to screen small molecules for their ability to improve ß-cell maturation and normalize insulin secretion. This project will unveil TNDM aetiology and will produce cellular tools with therapeutic and screening applications.