PROJECT SUMMARY Patients with long standing inflammatory bowel diseases (IBD) have an increased risk of colorectal cancer (CRC) as a consequence of chronic inflammation. To reduce morbidity and mortality from IBD-related CRC, surveillance for precancerous dysplasia with colonoscopy is recommended every 1-3 years beginning 8-10 years after diagnosis for most patients with IBD. However, the most effective way to perform dysplasia surveillance has not been definitively established. IBD-associated precancerous dysplastic lesions may represent a field effect from chronic inflammation and are difficult to see with standard definition white light colonoscopy. Fortunately, the advent of high-definition white light colonoscopy (HDWLC) improved our ability to visualize and remove precancerous dysplastic lesions. Nonetheless, the historical practice of collecting four untargeted random mucosal biopsies every 10 cm throughout the colon continues to be widely employed for patients with IBD. The rationale is that random biopsies may help detect these difficult to see precancerous lesions. However, the recommendations for this practice are based on uncontrolled observations and ex-vivo studies of resected specimen. In the one small randomized clinical trial to test the efficacy of random biopsies, the rate of dysplasia detection was numerically higher in the patients only getting targeted biopsies. This has led to equipoise regarding random biopsies. The proposed Utility of Random Biopsies in Inflammatory Bowel Disease (URBI) trial will be a multicenter pragmatic randomized clinical trial to definitively assess whether obtaining only eight random biopsies is non-inferior to the practice of obtaining four random biopsies every 10cm throughout the colon among patients with IBD undergoing dysplasia surveillance with HDWLC. The URBI trial will also present an opportunity to study the biology of colitis-associated dysplasia. Dysplasia is graded as absent, low-grade (LGD) or high-grade (HGD). Indefinite dysplasia (ID) is used when there is uncertainty whether or not there is LGD. Better understanding the biology of the dysplasia sequence could improve pathologic classification and minimizing the need for the ID category. Yet, little research has been done to understand the progression of inflammation to dysplasia or the molecular characteristics of ID using modern omics technologies. We will utilize new spatial molecular imaging techniques (imaging mass cytometry and spatial transcriptomics) and an integrative analytic approach to inform the biologic progression from inflammation to HGD, including the biology of ID. The biopsy samples and linked clinical data collected in the URBI trial will provide an ideal resource to study the molecular biology of colitis-associated dysplasia and ID. The URBI trial will establish best practices for IBD dysplasia surveillance and advance our understanding of the biology of colitis-associated dysplasia. This U34 grant will be used t...