Modelling Monogenic Diabetes using induced Pluripotent Stem Cells (iPSCs) (360G-Wellcome-203768_Z_16_A)

Diabetes is characterized by the body's inability to regulate blood glucose. Pancreatic beta-cells regulate glucose through insulin release. Monogenic Diabetes is a rare type of diabetes caused by single gene germline mutations that make beta-cells dysfunctional. Diagnosis with Monogenic diabetes is done through genetic testing. However, similar mutations can have different phenotypes and penetrance in families, underlying the need to address the pathophysiology of the mutations ex vivo. During my PhD project, I will analyse the data available for induced Pluripotent Stem Cells (iPSCs) derived from patients with Monogenic Diabetes banked through the Human Induced Pluripotent Stem Cells Initiative (HipSci). Mutant and healthy iPSCs lines will be differentiated towards pancreatic progenitors and beta-like cells, to determine their effect on pancreas development and beta-cell function. CRISPR-Cas9 will be employed to correct the mutations. The mechanism of action of the mutants will be investigated in vitro. The function of the corrected and mutant iPSCs differentiated towards beta-like cells will be addressed in vivo. This study should contribute towards understanding the heterogeneity of Monogenic Diabetes phenotypes. In the long-term, it could help towards a more accurate detection of Monogenic Diabetes and personalized treatment.