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Your Environment. Your Health.

THE ROLE OF NRF2 IN IMMUNE CELL POLARIZATION AND ALLERGY

Export to Word (http://www.niehs.nih.gov//portfolio/index.cfm/portfolio/grantdetail/grant_number/R01ES024966/format/word)
Principal Investigator: Rockwell, Cheryl Elizabeth
Institute Receiving Award Michigan State University
Location East Lansing, MI
Grant Number R01ES024966
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Feb 2016 to 31 Jan 2022
DESCRIPTION (provided by applicant):  : Over the last several decades, there has been a striking increase in the incidence of food allergies and other Th2-mediated disorders, such as asthma, in the U.S. and other western countries. Although environmental factors are thought to play a significant role in this alarming trend, the specific causative agent(s) remain to be identified. We recently demonstrated that tert-butylhydroquinone (tBHQ), a food additive present in many processed foods, promotes polarization of T cells towards a Th2 lineage, a key step in the development of allergy. Furthermore, our preliminary studies demonstrate that tBHQ, at concentrations relevant to human exposure, exacerbates food allergy in an animal model, suggesting a potential role for tBHQ in the increased incidence of food allergy in humans. In further support of this, human exposure to tBHQ in food and food packaging has been increasing since 1972, which is coincident with the increased incidence of food allergy in humans. Our objective in this application is to determine the mechanism by which the synthetic food additive, tBHQ, promotes polarization of CD4 T cells towards a Th2 lineage. Our central hypothesis is that tBHQ drives Th2 polarization through activation of a feed-forward transcriptional program requiring Nrf2 and GATA-3 that exacerbates the anaphylactic response to food allergen. This hypothesis is based upon our previously published studies and strong preliminary data, which demonstrate that activation of the transcription factor, Nrf2, by tBHQ promotes Th2 differentiation as evidenced by increased production of the Th2 cytokines, IL-4, IL-5 and IL-13, and increased expression and DNA binding of the Th2 master regulator, GATA-3, in isolated CD4 T cells. Furthermore, our preliminary studies show that mice exposed to tBHQ in the diet, at concentrations present in human food, have increased IgE and IgG1 production and an exacerbated anaphylactic response in a mouse model of food allergy. We propose to test our central hypothesis by 1) determining the mechanism by which activation of Nrf2 by tBHQ promotes Th2 differentiation, 2) determining the mechanism by which Nrf2 is induced during Th2 differentiation and 3) elucidating the mechanism by which tBHQ increases IgE and IgG1 production and exacerbates clinical signs of anaphylaxis in a mouse model of food allergy. Our results have important implications for defining the effect of tBHQ and other Nrf2 activators on Th2 polarization and allergy. In addition, we expect to identify the mechanism by which tBHQ regulates T cell differentiation and exacerbates anaphylactic response to food allergen. This information will be vital to mitigate the rise in food allergy and should help identfy new targets for allergy therapy.
Science Code(s)/Area of Science(s) Primary: 89 - ONES (Secondary only)
Publications See publications associated with this Grant.
Program Officer Michael Humble
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