The candidate is a pediatric gastroenterologist with strong training in patient-oriented research methodology, and a proven commitment to applying these methods to the study of the inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC). The candidate's long-term-career goal is to be an independently funded physician scientist, combining both traditional and genetic epidemiological methods to identify modifiable risk factors in genetically susceptible populations. The candidate's short-term career goals are 1) to acquire the necessary background in genetics, genetic epidemiology, pharmacoepidemiology, and research ethics in order to conduct studies of gene-environment interactions in pediatric IBD, 2) to develop the professional skills needed to successfully lead multidisciplinary research teams, and 3) to produce the critical mass of preliminary data and publications to be credible as the PI of an R01. The proposed research plan, career development activities, mentorship team, and institutional environment are all uniquely suited to assist the applicant in achieving these goals. Our overarching hypothesis is that CD risk is determined by complex interactions between 1) "early-life" exposures that impact the development of gut microbiota, 2) "disease-precipitating" exposures that may alter the microbiota, and 3) susceptibility genes which limit bacterial killing and allow persistent stimulation of an abnormal immune response. In this proposal, the PI will test the specific hypothesis that early-life exposure to antibiotics, which may disrupt the development of the microbiota, is a risk factor for CD, particularly in genetically susceptible individuals.
In Aim 1, the PI will conduct a retrospective birth cohort study including approximately 900,000 children born in Denmark between 1995 and 2007. Population-based prescription registries, patient registries, pathology databases, and other administrative data maintained by the Danish government will be used to measure the primary exposure, potential confounders, and outcomes of interest.
In Aim 2, the PI will establish the feasibility of a population-based case control study that combines traditional epidemiological methods with the additional collection of genetic data in order to assess gene-environment interactions. To support the candidate's career development, he will pursue advanced coursework and independent study in the areas of genetic epidemiology, pharmacoepidemiology, biostatistics, and research ethics. The mentorship team, which includes internationally-recognized, independently-funded investigators with expertise in gastrointestinal epidemiology (Sandler), genetic epidemiology (Millikan), IBD pathogenesis (Sartor), epidemiology methods (Sorensen), and research ethics (Dressler) will guide Dr. Kappelman's research and career development. The research environment including the UNC Translational and Clinical Sciences Institute and Center for Gastrointestinal Biology and Disease at UNC and the Department of Clinical Epidemiology at the University of Aarhus will provide a productive, collegial, and collaborative atmosphere in which to pursue the above research and training goals.

Public Health Relevance

Nearly 600 thousand Americans are affected by Crohn's disease (CD), a chronic, idiopathic, inflammatory bowel disease (IBD) that results in substantial morbidity including frequent hospitalization and surgery, missed work and school, and reductions in quality of life. The goal of this and subsequent research is to identify potentially modifiable risk factors in susceptible individuals. This could lead to strategies for disease prevention.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Podskalny, Judith M,
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Kappelman, Michael D; Farkas, Dora K; Long, Millie D et al. (2014) Risk of cancer in patients with inflammatory bowel diseases: a nationwide population-based cohort study with 30 years of follow-up evaluation. Clin Gastroenterol Hepatol 12:265-73.e1
Dellon, Evan S; Jensen, Elizabeth T; Martin, Christopher F et al. (2014) Prevalence of eosinophilic esophagitis in the United States. Clin Gastroenterol Hepatol 12:589-96.e1
Long, Millie D; Kappelman, Michael D; Martin, Christopher F et al. (2014) Risk factors for depression in the elderly inflammatory bowel disease population. J Crohns Colitis 8:113-9
Crockett, Seth D; Schectman, Robin; Stürmer, Til et al. (2014) Topiramate use does not reduce flares of inflammatory bowel disease. Dig Dis Sci 59:1535-43
Forrest, Christopher B; Crandall, Wallace V; Bailey, L Charles et al. (2014) Effectiveness of anti-TNF? for Crohn disease: research in a pediatric learning health system. Pediatrics 134:37-44
Cohen, Aaron B; Lee, Dale; Long, Millie D et al. (2013) Dietary patterns and self-reported associations of diet with symptoms of inflammatory bowel disease. Dig Dis Sci 58:1322-8
Long, M D; Martin, C; Sandler, R S et al. (2013) Increased risk of herpes zoster among 108 604 patients with inflammatory bowel disease. Aliment Pharmacol Ther 37:420-9
Long, Millie D; Farraye, Francis A; Okafor, Philip N et al. (2013) Increased risk of pneumocystis jiroveci pneumonia among patients with inflammatory bowel disease. Inflamm Bowel Dis 19:1018-24
Long, Millie D; Martin, Christopher; Sandler, Robert S et al. (2013) Increased risk of pneumonia among patients with inflammatory bowel disease. Am J Gastroenterol 108:240-8