This grant proposal describes a 5-year training program to develop the academic career of the principal investigator (PI) as an independent physician-scientist. The PI is a board-certified pediatric gastroenterologist at Ann & Robert H. Lurie Children's Hospital of Chicago (Chicago, IL) funded by an internal K award with a 75% effort for research allowing for career development as a physician-scientist. During the period of this proposal, the PI will continue translational research activities along with career development through Northwestern University programs and classes. Currently the PI is focused on studying the role of mast cells in inflammatory diseases of the gastrointestinal (GI) tract. The PI sees patients with inflammatory GI illnesses such as ulcerative colitis and eosinophilic esophagitis as well. The primary mentor is Associate Professor Paul Bryce, Ph.D., and the PI has remained a productive member of Dr. Bryce's laboratory since 2010. To enhance the training process, the PI will enlist a group of co- mentors with significant experience mentoring K08-awardees. This includes Robert Schleimer, Ph.D. whose has expertise in defining mechanisms of inflammation in human diseases, and two physician-scientists, Barry Wershil, M.D. a pediatric gastroenterologist, and Bruce Bochner, MD, an allergist-immunologist, both with an expertise in mast cell biology. This environment will maximize the potential for the PI to establish a scientifi niche for an academic career. The research proposal focuses on ulcerative colitis (UC), a type of inflammatory bowel disease (IBD), isolated to the colon, which causes chronic abdominal pain and bloody diarrhea, and ultimately, colon cancer. This disease affects both children and adults, and removal of the colon is the only curative therapy. Even with optimal medical therapy, many patients still require colon removal or suffer morbidity. Thus there remains a need to discover novel pathways that regulate the disease that offer therapeutic potential. The preliminary data suggests it may be beneficial to block the histamine 4-receptor (H4R) in UC by down-regulating interleukin-6 (IL6) mediated colonic inflammation. Mast cells function as tissue-resident powerhouses of inflammatory mediators, including histamine and IL-6, the latter of which is a drug target in IBD. This proposal will investigate the role and requirement of mast cell-derived mediators in colitis. The central hypothesis is: mast cells drive IL- 6 mediated colonic inflammation in UC via H4R. Two key aspects of the mechanism that remain unanswered are the cellular source of histamine and the cell in which H4R is activated to release IL-6. These two questions will be addressed in three aims, the first two will separately address the roles of mast cell-derived histamine and IL-6 utilizing mast cell reconstitution of mast cell-deficient mice in models of colitis, and the final aim is an analysis of cellular expression of H4R and IL-6 in UC biopsies and controls.
Ulcerative colitis (UC), a subtype of inflammatory bowel disease, is a chronic, relapsing colonic disorder with significant morbidities that include abdominal pain, bloody diarrhea and colon cancer. We have determined that the histamine 4-receptor (H4R) is up-regulated in human UC and that deficiency of H4R associates with reduced disease severity in two experimental models of UC. This proposal aims to determine the cellular source of histamine, along with the target cell in which H4R is activated to trigger te release of inflammatory mediators that drive UC pathogenesis.
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|Wechsler, J B; Szabo, A; Hsu, C L et al. (2018) Histamine drives severity of innate inflammation via histamine 4 receptor in murine experimental colitis. Mucosal Immunol 11:861-870|