Elucidating the Role of Cutaneous Environmental Factors in the Development of Allergic Disease

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Project Summary/Abstract This proposal describes a rigorous training program leading to the career development of Dr. Anna Eisenstein as an independent scientist. The principal investigator is a physician scientist who recently completed Dermatology residency. Her career goal is to become an independent investigator studying the interplay between the skin barrier and immune function, with a particular interest in allergic disease. She proposes to expand her training in immunology and allergy through an intensive research experience under the co-mentorship of Dr. Andrew Wang and Dr. Joseph Craft as well as a preeminent advisory committee with leading scientists and physician scientists in immunology and dermatology. In addition to excellent mentoring, the proposal includes rigorous coursework, seminars and external meetings. These planned activities will equip her with the necessary skills to become a successful independent investigator. The research objective of this proposal is to understand why individuals with atopic dermatitis (eczema) are more prone to food allergies, both conditions whose prevalence are exponentially rising. Preliminary data reveals that environmental xenobiotics, like common over-the-counter medications and food preservatives, act as allergic adjuvants both when given orally or applied topically. These products were all found to activate the xenobiotic receptor, Nuclear factor erythroid 2-related factor (Nrf2). Cutaneous disruption or topical application of Nrf2 activators was sufficient to induce sensitization to orally introduced food antigens, suggesting a novel mechanism of sensitization, distinct from the current epicutaneous paradigm wherein food allergens are thought to physically contact a damaged skin barrier to program the allergic immune response. The proposal will test the hypothesis that disruption of the skin barrier and/or topical chemical adjuvants that activate Nrf2 in keratinocytes promote epidermal production of alarmins, which signal on the intestinal epithelium and gut resident dendritic cells to initiate allergic sensitization to coincident non-tolerized oral allergens in a skin-gut-immune axis using a unique collection of full body and conditional knock out mice. This proposal serves as a training vehicle for Dr. Eisenstein to become an expert in immunobiology, mechanisms of allergic sensitization, and cutaneous barrier function so that she can apply this expertise to the field of dermatology and harmonize her clinical and research programs for maximal impact in translating her basic science investigations to the clinical management of atopic diseases. This project has the potential to explain the modern rise in incidence of food allergies as well as the clinical association between eczema and food allergies, which could lead to significant influence on public health and lead to novel therapeutic approaches to food allergy. Furthermore, these results may yield important novel insights into our fundamental understanding of the mechanisms of allergic sensitization.