FOR ADMINISTRATIVE SUPPLEMENT: COUNTERACT PROGRAM This administrative supplement application is an expansion of aim 3 of my parent R01 grant (ES025809) where we proposed experiments to examine AHR signaling regulation in macrophages and dendritic cells after treatment of our myeloid-specific Arnt-a (ARNT isoform 1) transgenic mouse model with AHR-activating toxicants. Recently, inhaled acrolein, a highly reactive a,b-unsaturated aldehyde and potent respiratory irritant, was shown to activate AHR in the lungs of exposed mice resulting in disruption of immune cell homeostasis. Thus, the focus of this supplemental project is to investigate effects of inhaled acrolein on AHR/ARNT signaling in alveolar macrophages and epithelial cells of Arnt-a transgenic mice versus non-carrier littermate controls. We predict that myeloid cells are central players in acrolein toxicity, and the experiments outlined in this application will provide clues to the mechanisms involved. Moreover, acrolein exposure experiments should significantly further our understanding of ARNT isoform-specific regulation of AHR as it pertains to maintaining immune homeostasis. To investigate our hypothesis, we propose to 1) Determine the role of AHR/ARNT signaling in response to acrolein exposure in lung macrophage and epithelial cell lines, in vitro, and 2) Determine the in vivo characteristics and magnitude of ARNT isoform 1-associated lung toxicity induced by inhaled acrolein in Arnt-a- transgenic mice.
FOR ADMINISTRATIVE SUPPLEMENT: COUNTERACT PROGRAM The experiments outlined in this supplemental proposal are focused on deciphering the regulatory roles of ARNT isoforms on AHR signaling in lung immune cells after exposure to acrolein, a potent respiratory toxicant. Given the environmental impact of the large-scale industrial production and use of acrolein, the potential for weaponizing acrolein, and the toxic levels of acrolein in tobacco and electronic cigarettes, we surmise that our supplemental project will positively impact public health. Furthermore, it is expected that this work will provide a rational basis for the future development of ARNT and AHR- based therapies for immune modulation for the treatment of toxicant-induced lung injury.
