Characterization of the Novel Protective Role of the Mast Cell in Colitis

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DESCRIPTION (provided by applicant): This proposal describes a 5 year training program for the development of the candidate as an independent scientist. Dr. Elizabeth Lennon is being trained as a member of the highly regarded Clinician Investigator program at North Carolina State University (NCSU). She completed structured residency training in veterinary internal medicine and obtained board certification in 2011. She then was accepted into a competitive fellowship supported by a Ruth L. Kirschstein Institutional Training Grant (T32) through the Center for Comparative Medicine and Translational Research, where she received excellent basic science training in Dr. Adam Moeser's laboratory, studying the role of the mast cell in inflammatory bowel disease (IBD). She is now proposing to expand her scientific skills in this understudied area of IBD research through an excellent mentorship team with complementary areas of expertise, receiving training in the use of axenic animals, high- throughput sequencing techniques, and multiplex analysis. Her proposed work aims to begin to unravel the complex role of the mast cell in IBD and that will progress our understanding of the pathophysiology of this disease in a direction that may lead to innovative early interventions and novel treatment strategies for IBD. The candidate's scientific development will be under the primary mentorship of Dr. Adam Moeser, Associate Professor of Gastrointestinal Biology, who is an innovative, R01-funded scientist who studies mast cell biology in the gastrointestinal tract. To enhance the training, Dr. Lennon will be co-mentored by Dr. Soman Abraham, Professor of Pathology, Immunology, and Microbiology and Director of Graduate Studies in Pathology at Duke University, and Dr. R. Balfour Sartor, Professor of Gastroenterology and Hepatology at the University of North Carolina at Chapel Hill (UNC). Both of these scientists have an excellent track record of R01 funding, including a MERIT award for Dr. Abraham. Both have mentored multiple K awardees and graduate students and are committed to providing excellent scientific and career advice, direction, and support to Dr. Lennon. Dr. Lennon will have access to many opportunities for professional development and career enhancement through continuing education, research seminars, journal clubs, and professional development lectures at NCSU and UNC. The proposal will aim to elucidate the novel protective role of the mast cell in IBD pathogenesis that has been demonstrated by the candidate's preliminary data. The candidate's recent work has demonstrated that mast cells have a protective role in spontaneous colitis; absence of mast cells in IL10-/- mice results in worsened colitis. Therefore, understanding the mechanism of this protective effect could lead to novel therapeutic or even preventative strategies for IBD patients or those who are predisposed. The central hypothesis is that mast cells are critical for dampening inflammation in IBD, and that mast cells suppress inflammation by induction of T regulatory cells (Tregs), which requires the presence of the intestinal microbiota. The specific aims of this work are: 1) This aim will demonstrate, in vivo, that MCs regulate colonic cytokine production and Treg number in colitis-prone mice, and that the intestinal microbiota influences MC-mediated recruitment and differentiation of Tregs in the colon. 2) This aim will address the hypothesis that MCs, following interaction with microbial products from the intestinal lumen, induce differentiation of naive CD4+ T cells into Tregs. This work will primarily be completed at NCSU, which provides excellent resources for completing all the studies proposed. Duke University will serve as a secondary site for specialized equipment use, and Dr. Lennon will receive additional training at the University of North Carolina at Chapel Hill. The College of Veterinary Medicine at NCSU provides an ideal setting for training veterinary clinician-scientists who are proficient in the use of and care for animal models of disease, and who can become leaders in comparative medicine, which can enhance discoveries that benefit human medicine as well. This environment maximizes the potential for Dr. Lennon to establish a scientific niche to form her transition to an independent research career.