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.

Public Health Relevance

This application is focused on understanding the pathogenesis of Crohn's disease using advances in imaging and patient-based research. The findings of this work may give rise to improved therapies for Crohn's disease, for IBD in general, and provide a paradigm for research related to other diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
NIH Director’s Pioneer Award (NDPA) (DP1)
Project #
5DP1DK109668-04
Application #
9534655
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Greenwel, Patricia
Project Start
2015-09-29
Project End
2020-07-31
Budget Start
2018-08-01
Budget End
2019-07-31
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Williams, Jesse W; Elvington, Andrew; Ivanov, Stoyan et al. (2017) Thermoneutrality but Not UCP1 Deficiency Suppresses Monocyte Mobilization Into Blood. Circ Res 121:662-676
Cifarelli, Vincenza; Ivanov, Stoyan; Xie, Yan et al. (2017) CD36 deficiency impairs the small intestinal barrier and induces subclinical inflammation in mice. Cell Mol Gastroenterol Hepatol 3:82-98
Ivanov, Stoyan; Randolph, Gwendalyn J (2017) Myeloid cells pave the way for lymphatic system development and maintenance. Pflugers Arch 469:465-472
Williams, Jesse W; Randolph, Gwendalyn J; Zinselmeyer, Bernd H (2017) A Polecat's View of Patrolling Monocytes. Circ Res 120:1699-1701
Randolph, Gwendalyn J; Bala, Shashi; Rahier, Jean-Fran├žois et al. (2016) Lymphoid Aggregates Remodel Lymphatic Collecting Vessels that Serve Mesenteric Lymph Nodes in Crohn Disease. Am J Pathol 186:3066-3073
Kim, Ki-Wook; Williams, Jesse W; Wang, Ya-Ting et al. (2016) MHC II+ resident peritoneal and pleural macrophages rely on IRF4 for development from circulating monocytes. J Exp Med 213:1951-9
Ivanov, Stoyan; Scallan, Joshua P; Kim, Ki-Wook et al. (2016) CCR7 and IRF4-dependent dendritic cells regulate lymphatic collecting vessel permeability. J Clin Invest 126:1581-91
Fonseca, Denise Morais da; Hand, Timothy W; Han, Seong-Ji et al. (2015) Microbiota-Dependent Sequelae of Acute Infection Compromise Tissue-Specific Immunity. Cell 163:354-66