An increasingly in-depth understanding of the microbiome and identification of susceptibility genes have changed the landscape for researchers seeking to reduce the health burden of inflammatory bowel disease (IBD). Despite these advances, and expanding detail of immunological activities in normal and diseased intestine, fundamental observations related to the course of disease in IBD remain starkly unexplained. For instance, key features of Crohn's disease include transmural inflammation, skip lesions characterized by the separation of inflamed and diseased intestinal segments with normal regions of intestine, and the proverbial creeping fat in which a tell-tale sign of the intensity of IBD is the appearance of fat that no longer stops at its usual boundary along the anti-mesenteric border but instead progressively creeps over and around the intestinal wall. None of these features are explained at a genetic, molecular, or cellular level, and yet surely they relate to the most harrowing complication of Crohn's disease: the formation of fibrostenotic lesions that serve as the principal cause for patients to be admitted to surgery, often emergency surgery to prevent bowel obstruction, and for which a large subgroup of patients experience repeatedly through the course of their disease. The work proposed will bring new approaches, conceptual and technical, to the study of IBD that have potential to transform our understanding of human Crohn's disease as a major form of IBD. The overarching hypothesis is that blood vessel remodeling is at the core of the disease, that it has in part an immunological basis, and that its remodeling goes hand-in-hand with alterations in the lymphatic vasculature that in turn contributes to disease pathogenesis and fibrosis. We will carry out patient-based studies to address this hypothesis.