Understanding the role of islet development in type 2 diabetes susceptibility. (360G-Wellcome-109108_Z_15_A)

Genome-wide association studies (GWAS) have found over 100 loci associated with type 2 diabetes (T2D), but the causal mechanisms of the disease remain unclear. Pancreatic islets play a role in the development of T2D, and although the contribution of developmental processes to disease susceptibility has not yet been established, several of the GWAS loci localise near known genes for islet development. I will investigate the role of islet development in T2D susceptibility through analysis of iPSC differentiation models of human endocrine pancreas cells (concretely, beta-cells). I will use transcriptomic and regulatory information to identify genes involved in their development, finding the most influential genes in each stage of differentiation, and characterizing temporal patterns and networks of gene expression. I will investigate specially the presence and abundance of genes located in T2D or fasting glucose -associated loci. The bioinformatics analyses will generate a list of important genes for endocrine pancreas development. I will then evaluate experimentally the function of some of these genes in development and T2D risk. Using CRISPR to modulate the expression of candidate targets in specific stages of development, either activating or interfering gene expression, I will measure how this alters the transcriptome and beta-cell differentiation.