Impact of Aryl Hydrocarbon Receptor Ligand Ingestion on Gastrointestinal Immunity

My career goal is to become an independent, R01 funded investigator in the field of mucosal immunology of the gastrointestinal tract. This objective will be reached through the execution of a specific career development plan that will allow me to gain the necessary training and laboratory skills as well as establish an independent line of investigation for future grant applications. My mentor Dr. Fiebiger and Co- mentor Dr. Lencer are carefully chosen to ensure optimal training in gastrointestinal immunology and intestinal epithelial cell biology, respectively. Further enrichment will be provided by biannual meetings with a scientific advisory committee, including Drs. Marian Neutra, Richard Blumberg and Scot Snaper, all highly accomplished investigators in the areas of mucosal immunology and gastroenterology. Environment: My career development as well as my project wil benefit from the uniquely rich research environment of Harvard Medical School and affiliated hospitals. The laboratories of my mentors provide al relevant state of the art equipment for the project and the Harvard Digestive Disease Center offers additional opportunities for collaborations and scientific interactions.<P> Research: The proposed project addresses a big gap in our understanding of aryl hydrocarbon receptor (AhR) activation in the gastrointestinal (GI) tract. The AhR is a cytosolic receptor activated by many molecules, including environmental toxins and drugs that are ingested. Upon activation AhR translocates into the nucleus and functions as a transcription factor. Transcriptional events controlled by AhR have been shown to have various effects on immune responses. However, the effects of AhR activation on gastrointestinal immune responses have not yet been defined. Epidemiologic studies show a rise in recent years of food alergy, a condition in which the gastrointestinal immune system plays an important role. This could be due in part to increased exposure to environmental pollutants and drugs, which target the AhR.<P> We here hypothesize that AhR activation impacts the development and severity of inflammatory immune responses associated with food allergy. Two complementary in vitro and in vivo aims are proposed in this application to determine whether AhR ligands promote food allergic responses by changing the mucosal microenvironment through activation of AhR in dendritic cells and intestinal epithelial cells, two key cell types for the regulation of mucosal immunity. <P>We will compare AhR activation induced by AhR ligands of two distinct ligand classes relevant for human health: (1) the environmental pollutant dioxin and (2) the drug omeprazole. Omeprazole, in particular, is interesting, because recently de novo allergic sensitization in adult was correlated with use of acid suppressive medications. Specifically, this study proposes in Aim 1 to define the consequences of AhR activation for immune effector functions of mucosal DCs and intestinal epithelial cells on a cellular level in vitro. The objective of Aim 2 is to determine the impact of AhR ligands on the development of food allergy using a newly established Fc?RI transgenic mouse model, which IgE receptor expression pattern closely reflects that of humans and thus represents an optimized animal model for studying allergic diseases. In summary, our strategy has a high likelihood of leading to new insights into the role of AhR activation in the context of GI immunity. Findings of this project could also provide a basis to develop therapeutic strategies to prevent and/or treat food allergic responses through inhibition of AhR activation via natural or chemical AhR antagonists.