Inflammatory bowel disease (IBD) affects approximately 1.4 million people in the United States, and carries numerous and severe complications, such as fistulas, strictures, and heightened risk of colorectal cancer. The purported explanation of IBD is a persistent inappropriate activation of the immune system possibly triggered by the microbiota. Indeed, the intestinal epithelium is continually exposed to and challenged by a tremendous antigen load. Remarkably, the intestinal epithelium maintains homeostasis despite continually sustaining injury. Defects in wound healing programs are emerging as playing a key role in contributing to IBD pathogenesis. Wound healing programs remain complex, however, and the genetic factors in play have yet to be firmly established. Epithelial-to-mesenchymal transition (EMT) is a critical process by which epithelial cells acquire more mesenchymal phenotypes, such as greater motility and anchorage independence, and it is pivotal in injury repair. Blood vessel epicardial substance (BVES) is a tight junction associated protein discovered in a cDNA screen of a developing heart. Recently, it has been demonstrated that loss of BVES promotes EMT in corneal epithelial and malignant cell lines. Furthermore, knocking down BVES expression disrupts cell-to-cell adhesion, accelerates migration, invasion, and anchorage independent growth and increases proliferation. Interestingly, aberrant EMT programs have recently been implicated in the pathogenesis of IBD. Given these observations we postulate that BVES could contribute to the pathogenesis of IBD. In support of this, we found that BVES levels in IBD patients were inversely correlated to disease severity. Taken together, we hypothesize that BVES plays a critical role in epithelial repair programs. We propose to test this hypothesis and expand our understanding of how BVES informs intracellular signaling pathways by two focused specific aims. First, we will induce intestinal injury in BVES-/- mice using two complementary animals models of colitis: dextran sodium sulfate (DSS) and Citrobacter rodentium infection. These will allow us to determine whether BVES deficient mice are more susceptible to colitis. Second, we have commissioned a yeast-two-hybrid screen and identified PR61-alpha, a phosphatase linked to cell growth and proliferation, as a binding partner of BVES. We will test the functional significance of this interaction by mapping the binding domains and by determining how disrupting the interaction affects BVES-dependent phenotypes and intracellular signaling. Our proposed studies will define the role of BVES in IBD pathology and injury repair programs. Importantly, clarifying the role of BVES could potentially create new avenues of therapy.

Public Health Relevance

Project Narrative Inflammatory bowel disease (IBD) affects approximately 1.4 million individuals in the United States, and despite exciting advances in recent IBD research, we still lack a complete understanding of the disease, impeding breakthroughs in treatment. Our data suggests that BVES, a protein involved in forming cell-to-cell interactions, may contribute to IBD. We propose to investigate thoroughly the contribution of BVES to IBD by using animal models as well as cellular experimentation with the ultimate goal of deciphering how BVES can be targeted therapeutically.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Special Emphasis Panel (ZDK1-GRB-2 (O1))
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Podskalny, Judith M,
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Vanderbilt University Medical Center
Internal Medicine/Medicine
Schools of Medicine
United States
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Parang, Bobak; Kaz, Andrew M; Barrett, Caitlyn W et al. (2017) BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis. Gut 66:852-862
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