Mucosal remodeling with villous atrophy is a generic response to small intestinal injury with many causes that require different treatments. While easily recognized on intestinal biopsy specimens, determining the specific cause of villous atrophy is more challenging and often leads to therapeutic delays. This Career Development Award is based upon the hypothesis that transcriptomics can both elucidate mechanisms of villous atrophy across diseases and provide improved tools for diagnosis and monitoring. Jocelyn A. Silvester, MD PhD is Instructor at Harvard Medical School and a subspecialist within the Celiac Disease Program at Boston Children's Hospital. She has gained substantial basic and clinical research experience during her doctoral and medical training and has demonstrated commitment to an academic career in patient oriented research. This Career Development Award will provide additional mentored training and research opportunities in bioinformatics and mucosal immunology for Dr Silvester to advance her quantitative research skills while addressing the current knowledge gap related to mechanisms of small intestinal epithelial injury and the lack of disease-specific biomarkers of villous atrophy. Dr Ciarn Kelly, an acknowledged expert in celiac disease and intestinal inflammation, and Dr Isaac Kohane, an expert in bioinformatics and quantitative biology, will serve as mentors. In addition an Advisory Committee comprised of experts across multiple relevant disciplines (Drs Leffler, Lencer, Goldsmith, and Fasano) will meet with the applicant and mentors regularly to assess progress. This award will aid Dr Silvester in establishing an independent research program as an academic physician- scientist through a structured training plan that includes formal course work in bioinformatics and statistics, as well as relevant clinical research in functional genomics. She will also receive additional training in quantitative interpretation of intestinal histology and grant writing to facilitate her goal of using insights from large-scale genomic data to improve diagnosis, treatment, and outcomes for patients with celiac disease and other enteropathies. The research at the foundation of this application aims to characterize the different mechanisms leading to villous atrophy and to identify a molecular signature of celiac disease activity in peripheral blood. Celiac disease will be used as a model to study the time course of changes occurring as villous atrophy recurs during gluten challenge in celiac patients who had recovered on a gluten-free diet. Additionally, comparative transcriptomic studies will be performed using intestinal tissue from patients with celiac disease, adult-onset autoimmune enteropathy and drug-induced (olmesartan) enteropathy. Finally, we will study peripheral blood mRNA markers of villous atrophy in participants in our ongoing Manitoba Celiac Disease Cohort study undergoing protocol biopsy 24 months after starting a gluten-free diet. The substantial research, educational and clinical resources of Boston Children's Hospital, Harvard Medical School and the Harvard Celiac Research Program are committed to the applicant to ensure successful attainment of the goals of this award.
This career development award addresses a major gap in our knowledge of mechanisms of villous atrophy, which is a clinically important response to injury to the small intestinal epithelial lining characterized by increased permeability (a leaky intestine) and loss of proper function of intestinal lining cells. We hypothesize that transcriptomics (analysis of gene expression) can both elucidate mechanisms of villous atrophy across diseases and provide improved tools for diagnosis and monitoring. A peripheral blood biomarker of villous atrophy will be an extremely valuable tool for diagnosis and monitoring of treatment response, both in clinical practice and in clinical trials of new treatments.