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Flavin-containing monooxygenases (FMOs) are conserved intracellular enzymes that oxidize organic molecules and produce reactive oxygen species (ROS). We recently discovered that FMOs are important innate host defense effectors. This project uses an in vivo reductionist approach in Caenorhabditis elegans as model organism to improve understanding of the host defense functions of FMOs. The long-term goal of this project is to understand how C. elegans and mammalian FMOs are regulated and how they promote host defense during infection. Our prior research supports the idea that C. elegans FMO-2, human FMO5, and other FMOs may possess evolutionarily conserved functions in host-microbe interactions. What these functions are and how they are regulated is currently unknown. This is an important fundamental knowledge gap that impedes understanding of homeostasis and host defense in animals, and that obscures therapeutic opportunities to treat infections or inflammatory diseases. The overall objectives of this developmental project are to increase mechanistic understanding of FMO-2/FMO5 function in the context of host defense against bacterial infection and to develop novel approaches and model organisms that enable future studies to elucidate the roles and regulation of FMOs in C. elegans and mammalian innate immunity. This project’s central hypothesis is that distal NHR-49/PPAR-a signals through INS-19 to induce FMO-2/FMO5 in the intestinal epithelium, triggering FMO-2-dependent antimicrobial mechanisms. To test this hypothesis, we will define upstream mechanisms of fmo-2/FMO5 gene regulation and downstream mechanisms of FMO-2/FMO5-mediated host defense. The proposed research is technically innovative because of innovations in the application of new methods to determine peroxidized lipids in C. elegans, for the use of synthetic lethality to uncover specific and genetically redundant tissues of action, and for use of genetic complementation for in vivo functional evaluation of reconstructed ancient mammalian FMOs in C. elegans. Additionally, the proposed work is conceptually innovative for connecting NHR-49/PPAR-a to HLH-30/TFEB via insulin/insulin-like growth factor INS-19 for the induction of FMO-2/FMO5 (potentially revealing a novel mechanism connecting organismal metabolism and innate immunity) and for its proposed role for FMO-2/FMO5 as source of ROS and oxidized signaling lipids during infection. This proposal is highly relevant to human health because it focuses on genes and pathways that are conserved in humans. This proposal is highly significant because it directly addresses the important gap in fundamental knowledge of FMO roles and regulation as innate immunity effectors. Moreover, the reagents, assays, new model organisms, and knowledge gained through this developmental project will open new avenues of research into innate immunity and FMO function and help create a path forward for the rational design of host-directed therapeutics against bacterial infections and microbiota dysbiosis. Therefore, this proposal is highly relevant to human health, and we expect this project to have an important and broad positive impact.
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