FLAVIN-CONTAINING MONO-OXYGENASES AS NOVEL INNATE IMMUNITY EFFECTORS

含黄素单加氧酶作为新型先天免疫效应物

• 批准号: 10682077
• 负责人: Javier Elbio Irazoqui
• 金额: $ 25.13万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682077
• 关键词: Address; Aging; Bacteria; Bacterial Infections; Biological Assay; Body Weight; Brain; Caenorhabditis; Communication; Data; Defect; Disease; Eating; Enzymes; Future; Genes; Genetic; Genomics; Hepatic; High Fat Diet; Homeostasis; Homo; Host Defense; Host Defense Mechanism; Human; Infection; Ink; Intestines; Label; Mediating; Mediator; Membrane Transport Proteins; Methods; Mission; Mixed Function Oxygenases; Mus; Natural Immunity; Nervous System; Neurons; Organism; Outcome; PPAR alpha; Pathway interactions; Pattern; Peptides; Reactive Oxygen Species; Reagent; Research; Research Support; Resistance; Site; Source; Stress; Testing; Therapeutic; Tissues; Work; Xenobiotics; design; dysbiosis; flavin-containing monooxygenase; gut-brain axis; host-microbe interactions; human disease; improved; in vivo; innovation; intestinal epithelium; microbiota; novel; overexpression; oxidation; peroxidation; prevent; protective effect; therapeutic target

F"avin-containing monooxygenases (FMOs) are conserved intrace""u"ar enzymes that oxidize organic mo"e- cu"es, such as xenobiotics, and promote their export by p"asma membrane transporters. We recent"y discov- ered that FMOs are important innate host defense effectors. This project uses an in vivo reductionist approach with Caenorhabditis e5egans as mode5 organism to improve understanding of the host defense functions of FMOs. The "ong-term goa" of this project is to understand how C. e5egans and mamma"ian FMOs are regu- "ated and how they promote host defense during infection. Our prior research supports the idea that C. e5e- gans FMO-D, human FMOE, and other FMOs may possess evo"utionari"y conserved functions in host-microbe interactions. What these functions are and how they are regu5ated is current5y unknown. This is an important fundamenta" know"edge gap that impedes understanding of homeostasis and host defense in anima"s, and that obscures therapeutic opportunities to treat infections or inf"ammatory diseases. The overa"" objective of this deve"opmenta" app"ication is to increase mechanistic understanding of FMO-D/FMOE function in the con- text of host defense against bacteria" infection and to deve"op nove" approaches and mode" organisms, thus enab"ing future studies to e"ucidate the ro"es and regu"ation of FMOs in C. e5egans and mamma"ian innate im- munity. This project’s centra" hypothesis is that HLH-CD/TFEB and NHR-JK/PPAR-α induce expression of FMO-P/FMOQ for host defense via FMO-P activity-dependent antimicrobia5 mechanisms. To test this hypothe- sis, we wi"" Define upstream mechanisms of fmo-P/FMOQ gene regu"ation and downstream mechanisms of FMO-D/FMOE-mediated host defense. The proposed research is technica""y innovative because of innovations in the app"ication of new methods to determine peroxidized "ipids in C. e5egans, for the use of synthetic "etha"- ity to uncover specific and genetica""y redundant tissues of action, and for use of genetic comp"ementation for in vivo functiona" eva"uation of reconstructed ancient mamma"ian FMOs in C. e5egans. Additiona""y, the pro- posed work is conceptua""y innovative for connecting HLH-MN/TFEB to NHR-ST/PPAR-α for the regu"ation of FMO-D/FMOE (revea"ing a nove" connection between metabo"ism and innate immunity) and for its proposed ro"e for FMO-D/FMOE as source of ROS and oxidized signa"ing "ipids during infection. This proposa" is high"y re"evant to human hea"th because it focuses on genes and pathways that are conserved in humans. This pro- posa" is high"y significant because it direct"y addresses the important gap in fundamenta" know"edge of FMO ro"es and regu"ation as innate immunity effectors. Moreover, the reagents, assays, new mode" organisms, and know"edge gained through this deve"opmenta" project wi"" open new avenues of research into innate immunity and FMO function and he"p create a path forward for the rationa" design of host-directed therapeutics against bacteria" infections and microbiota dysbiosis. Therefore, this proposa" is high"y re"evant to human hea"th, and we expect this project to have an important and broad positive impact.

含Avin的单加氧酶(FMOS)是一种保守的氧化有机钼的酶。 铜，如外来生物物质，并通过p“Asma膜转运体促进其出口。我们最近发现了- 他认为FMO是重要的天然宿主防御效应器。这个项目使用体内简化论的方法。 以秀丽隐杆线虫为模型生物提高对线虫寄主防御功能的认识 FMO。这个项目的“长期目标”是要了解蚊子和妈妈们是如何调整的-- 以及它们如何在感染过程中促进宿主防御。我们之前的研究支持这样的观点，即C.e5e- Gans FMO-D、人FMOE和其他FMO可能在宿主微生物中具有Evo保守功能 互动。这些功能是什么以及它们是如何被调整的，目前尚不清楚。这是一个重要的 基本的“知道”的边缘差距，阻碍了对动植物体内平衡和宿主防御的理解“S，以及 这掩盖了治疗感染或炎症性疾病的治疗机会。 这一开发应用的目的是增加对FMO-D/FMOE在环境中的作用的机理的理解。 寄主防御细菌感染的文本和开发新的方法和模式的生物体，从而 开展未来的研究，以确定FMOS在弓形虫和母体中的作用和调节 社区生活。本项目的中心假设是hLHCD/TFEB和NHR-JK/PPAR-α诱导HLHCD/TFEB和NHR-JK/PPAR-TFEB表达。 FMO-P/FMOQ通过FMO-P活性依赖的抗菌素5机制进行宿主防御。为了检验这个假说- SIS，我们将定义FMO-P/FMOQ基因的上游调控机制和FMO-P/FMOQ基因的下游调控机制 FMO-D/FMOE介导的宿主防御。建议的研究因创新而具有技术创新性。 在应用新的方法来确定C。e5egans中的过氧化的IPID，用于合成的“etha”- 有能力发现特定的和遗传的多余的作用组织，并利用基因复合来 在活体内评价重建的古代哺乳动物的Ian FMOS在C.egans.Additiona“y”中的作用。 提出的工作是一种创新的概念，将HLHMN/TFEB连接到NHR-ST/PPAR-α，用于规则 FMO-D/FMOE(揭示代谢与先天免疫之间的“新”联系)及其建议 在感染过程中，FMO-D/FMOE是ROS和氧化信号的来源。这一建议是高的。 Re“Evant to Human Hea”th是因为它关注的是在人类体内保守的基因和途径。这位亲王- POSA是高度重要的，因为它直接解决了FMO的基本知道边缘的重要差距 作为先天免疫效应器的Res和Regu。此外，试剂、化验、新模式“生物”和 了解“通过这一发展获得的优势”Opmenta“Project wi”打开了研究先天免疫的新途径 和FMO功能，并为宿主导向疗法的理性设计创造了一条前进的道路 细菌感染和微生物区系失调。因此，这一建议对人类健康是高度有益的，并且 我们期待这一项目将产生重要和广泛的积极影响。