This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The objective of this COBRE subproject is to provide a detailed analysis of the role of the aryl hydrocarbon receptor (AhR) in regulating pulmonary inflammation in response to harmful particulates through its interactions with components of the Nlrp3 inflammasome. The proposed research will significantly improve our understanding of chronic inflammatory disorders and will generate unique and high impact information regarding how the AhR regulates pulmonary inflammation in the context of animal models of human disease. It will also advance our basic understanding of the role of the AhR in lung function and pulmonary immunity. In the first aim, we will define the role of the AhR in the regulation of inflammatory signaling both in vitro and in vivo in response to harmful particulates. In the second aim, using TCDD and various other ligands of the AhR, we will demonstrate that AhR activation regulates inflammatory signaling. In the third specific aim, we will identify the nature and molecular components of the inflammasome-AhR interface that regulate the generation of an inflammatory environment. This study deals with a novel regulatory system for inflammasome signaling in which the AhR negatively regulates the inflammatory responses induced by harmful particulates. Improved knowledge regarding mechanisms for suppressing inflammasome activation and chronic inflammation via AhR activation will provide rationale targets for development of therapeutics. Furthermore, this application is innovative in that it is expected to contribute to the development of novel therapeutic targets for the management of respiratory illnesses, including particulate-induced inflammation and fibrosis, which would have a significant, positive effect on human health.
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