A. Personal Statement

The focus of my research program over the past 25 years has been to discover underlying mechanisms and better therapeutic approaches for patients with Inflammatory Bowel Disease (IBD), with a particular focus upon disease complications in patients with Crohn’s Disease (CD).  I have served as co-PI for three large pediatric IBD inception cohort studies, CAMEO, PROTECT, and RISK.  These studies have identified host and microbial mechanisms which drive mucosal inflammation and CD complications including strictures (Kugathasan et al Lancet 2017) and are guiding the development of new microbial-targeted therapies (Ta et al IBDJ 2021), including the 2'-Fucosyllactose RCT which I am leading.   In this context, we discovered that adult and pediatric CD patients with elevated levels of neutralizing GM-CSF autoantibodies were more likely to develop ileal strictures requiring surgery and have developed a clinical assay which may be used for patient classification (Han et al Gastroenterology 2009). We have now used genomic observations (Denson et al Gastroenterology 2018) from these cohort studies to develop a novel human intestinal organoid model system to test pathogenic mechanisms, and potential small molecule therapeutics (Haberman et al JCC 2020), for fibrostenotic CD (Jurickova et al IBDJ 2022, Jurickova et al JCC 2024).  I am actively collaborating with our Center for Stem Cell and Organoid Medicine (CuSTOM) faculty in the application of this CD model system.  We have formed a highly productive collaboration to apply deep learning to classification of inflammatory gut disorders.  These exciting studies have formed the basis for the current work, in which we will collaborate to apply state-of-the-art data science and multiomic approaches to inform cells and pathways to test as we further develop and validate a CD patient induced pluripotent stem cell-derived macrophage:human intestinal organoid model system.  We envision that this combinatorial New Approach Methodology will advance personalized health to address the rapid growth in biological therapeutics, while incorporating population diversity and sex as a biological variable.