To gain insight into IBD mechanisms and to improve the development of new therapeutics, an understanding of how genetic factors modulate intestinal homeostasis is required. We propose to model human IBD pathogenesis using gene editing in human embryonic stem cell-derived organoids to generate lines carrying mutations associated with IBD susceptibility. First, we will establish human intestinal organoids (HIOs) carrying five IBD susceptibility genes and study their development, thereby gaining unprecedented insights to the molecular and cellular mechanisms of IBD in human cells, which will illuminate patient phenotypes at the level of genes, cells, and tissues. Second, we will learn how IBD susceptibility genes participate in control responses to cellular stress and contribute to tissue regeneration following injury, leading to a better understanding of intestinal homeostasis and its disruption in IBD. In the long run, we will use the information gained in this study to develop a screening platform as a powerful tool for identifying small molecules with therapeutic potential, which will pave the way to improved IBD medicines.