The overarching goal of this career development award is to provide a comprehensive training program to prepare me for an independently funded translational research career focused on the immunopathogenesis of pediatric inflammatory bowel disease (IBD). I am an Assistant Professor of Pediatrics and board-certified pediatric gastroenterologist with an advanced degree in patient-oriented research (Masters of Science in Clinical Investigation, MSCI). My near-term goal is to acquire additional expertise in mucosal immunology and functional genetics while continuing a productive line of investigation into the role of Th2 inflammation in pediatric IBD. This award will allow me to meet this goal with formal graduate-level coursework, workshops in key techniques such as flow-cytometry and gene expression assays, and protection for 5 years of mentored research. My primary mentor is Keith Wilson, MD, who has a well-established track record of high impact research in translational mucosal immunology related to IBD and H. Pylori. My career development is further benefited by two co-mentors; Luc Van Kaer, PhD, an immunologist internationally recognized for his expertise in natural killer T cells, adaptive immunity, and mucosal immunology, and R. Stokes Peebles, Jr., MD, a physician-scientist who is an expert on Th2 inflammatory responses. Vanderbilt University Medical Center provides a rich environment for research and the training of young investigators with centralized oversight of all mentored physician scientists through the Office of Clinical & Translational Scientist Development. Furthermore, my laboratory is embedded within the highly productive NIH P30 funded Vanderbilt Digestive Disease Research Center (DDRC), which will provide further enrichment though regular interaction with other DDRC investigators, invited speakers, and access to state-of-the-art core laboratory facilities. My long-term goal is to become an independently-funded physician-scientist with the unique skills and training to bridge both human and animal studies within a large translational IBD research program that will impact the care of patients with this disease. The strong mentorship, additional training, and environment detailed in this proposal will position me to ultimately reach this objective. The research proposal extends my prior published work on the role of Th2 inflammation in pediatric IBD. Ulcerative colitis (UC) and Crohn's Disease (CD), are chronic inflammatory disorders of the intestine that affect 1.5 million Americans, 50,000 of whom are children. The advent of anti-TNF therapy marked a major advance in treatment; however, the substantial number of UC patients refractory to anti-TNF therapy suggests that other inflammatory pathways can drive the disease. Classically, the intestinal mucosa in CD has been associated with Th1 and Th17 inflammatory responses, while the mucosa in UC is associated with atypical Th2 inflammation. This distinction may explain the disease refractoriness of many UC patients and the 20% colectomy rate for pediatric UC. In fact, monoclonal antibodies against IL-13, a proposed pathogenic Th2 cytokine, are in phase 2 trials for UC. Therefore, it will be important to identify those UC patients with upregulated Th2 responses who may most benefit from future Th2-directed therapy. Accordingly, our analysis of preliminary genome-wide expression data suggests that expression of certain Th2-related genes distinguishes pediatric UC from Crohn's colitis, and that high expression of transcripts for IL-13 receptor ?2, IL- 33, and the IL-33 receptor, ST2, is associated with refractoriness to 5-aminosalycilate (5-ASA) therapy. IL-33 is a potent inducer of Th2 cytokines and is increased in UC, but its role in UC pathogenesis is not clear. Our data show that in the Th2-driven murine oxazolone colitis, there is increased epithelial- and macrophage-derived IL- 33, and that STAT6-/- mice exhibit decreased colitis severity correlated to reduced IL-33 expression. We hypothesize that a subset of pediatric UC patients exhibits an upregulated Th2 mucosal immune response. Furthermore, we propose that IL-33, as a potent inducer of Th2 cytokine production, is a driver of murine Th2- mediated colitis and associated with disease refractoriness in human UC.
In Aim 1, we will determine whether a subset of pediatric UC patients exhibit heightened Th2 inflammatory responses, and whether this predicts response to 5-ASA therapy. Our approach will be to analyze mucosal expression of a focused set of genes involved in Th2 inflammation in a large pediatric IBD inception from the CCFA Pediatric Network with detailed prospective outcomes data. Tissues from Vanderbilt pediatric IBD patients will be used to validate findings at the protein level.
In Aim2, we will determine the role of IL-33 in influencing innate and adaptive immune mechanisms in murine colitis by inducing oxazolone colitis in IL-33-/- mice, ST2-/- mice, and mice treated with soluble ST2 fusion protein. This project will advance our understanding of the influence of Th2 inflammation on therapeutic outcome in children with IBD and determine the potential of the Th2-inducing cytokine IL-33 as a target for future UC therapy.
The inflammatory bowel diseases, comprised of ulcerative colitis and Crohn's disease, affect 1 million Americans, 50,000 of whom are children. Current medical therapy, directed mainly at the inflammatory cytokine TNF, is ineffective for a substantial number of patients. By understanding the role of alternative cytokines or inflammatory pathways in specific forms of pediatric inflammatory bowel disease, we can identify new targets for future medical therapies.
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