Investigation of the Transforming Growth Factor Beta Pathway in Eosinophilic Esophagitis

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 DESCRIPTION (provided by applicant): This proposal is designed to provide the Principal Investigator, Anthony L. Guerrerio, with the necessary knowledge, skills, infrastructure and experience required to transition to a position as an independent researcher in the field of pediatric gastroenterology, focusing on mucosal immunology and its role in oral tolerance and the development of Eosinophilic Esophagitis (EoE). Dr. Guerrerio outlines a five-year plan to investigate the basic mechanism by which mutations in the TGFβ receptor lead to immune dysregulation and the development of EoE. This work will be performed under the mentorship of Dr. Harry C Dietz, Victor McKusick Professor of Medicine and Genetics and Investigator in the Howard Hughes Medical Institute at Johns Hopkins University. Dr. Dietz has an impressive track record of mentoring young investigators for successful careers in academic medicine, including those funded under the K award mechanism. Dr. Guerrerio also has the support of a team of extraordinary physician scientists at Johns Hopkins including Drs. Cynthia Sears and David Huso. All of these individuals have committed their time, resources, and expertise to facilitate Dr. Guerrerio's career development and research goals. In addition, the candidate will acquire additional skills and training through didactic coursework at the highly regarded Johns Hopkins Bloomberg School of Public Health. The candidate's past academic experiences underscore his commitment to academic medicine and his desire to acquire rigorous and complete scientific training. He completed a MS in physics, then entered the NIH-sponsored Medical Scientist Training Program at Johns Hopkins University and did his graduate work under the mentorship of Dr. Jeremy Berg in the Department of Molecular Biophysics. There he performed basic research investigating the molecular events that allow intracellular zinc-sensing by a metal responsive transcription factor. He also developed a method of targeting proteins to a single-stranded region of DNA, which may have therapeutic applications. He completed both a residency in Pediatrics and a fellowship in Pediatric Gastroenterology at Johns Hopkins University. During fellowship, he became interested in the role of choline, a small quaternary amine now known to be an essential nutrient for humans. He completed a small clinical trial in children with intestinal failure that revealed a high prevalenc of choline deficiency in this population, and suggested that intravenous delivery of choline may be required to replete choline in this population. This study also defined normal plasma choline percentiles by age for the first time. He also demonstrated a role for choline deficiency in the development of fibrosis in post-menopausal women with nonalcoholic steatohepatitis (NASH). Returning to the lab, Dr. Guerrerio became interested in the mucosal immune system and how inappropriate immune activation can lead to EoE. This interest crystalized around the characterization of Loeys-Dietz Syndrome (LDS), a newly described autosomal dominant disorder caused by mutations in the genes encoding the receptor subunits for TGFβ. LDS is associated with an increased risk of developing EoE and other more general food allergies. Remarkably, LDS mice also demonstrate increased Th2 inflammation, and the spontaneous development of EoE. Dr. Guerrerio joined the faculty at Johns Hopkins as an Assistant Professor in July 2009. His research experiences have afforded him with a unique background in molecular biology, biochemistry, immunology, and both human and murine models of disease. He is now poised to apply these skills, under the guidance of his mentors, to study the basic mechanisms underlying the development of EoE. The research in this proposal will focus on the role of the TGFβ pathway and its interplay between the cell types of the esophagus using LDS mice as a model system. Aims include: 1) To define the role of lymphocytes and Tregs in the development of EoE in LDS and how signaling alterations in these cells lead to inappropriate production of Th2 cytokines, 2) Investigate the role of epithelia cells and other nonhematopoietic cells in the development of EoE in LDS, and 3) Define the signaling defect in lymphocytes carrying the LDS mutation and test whether pharmacologic inhibition of TGFβ signaling mitigates the EoE phenotype. The scientific training obtained through this grant will lead to publications, data, and experience that will enable the candidate t secure independent NIH funding within the next 4-5 years and establish himself as an independent physician scientist.