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.

含禽素单加氧酶（FMO）是保守的酶内酶，其氧化有机分子 我们最近发现，例如异生物质，并通过 p“asma 膜转运蛋白促进它们的输出。 认为 FMO 是重要的先天宿主防御效应器，该项目使用体内还原方法。 以Caenorhabditis e5egans作为mode5生物体，以提高对宿主防御功能的了解 该项目的“长期目标”是了解 C. e5egans 和 mamma"ian FMO 是如何调节的。 “以及它们在感染期间如何促进宿主防御。我们之前的研究支持 C. e5e- 甘斯FMO-D、人类FMOE和其他FMO可能在宿主微生物中具有进化保守功能 这些功能是什么以及它们如何调节目前尚不清楚。 阻碍对动漫中稳态和宿主防御的理解的基础“知识”边缘差距，以及 这掩盖了治疗感染或炎症性疾病的治疗机会。总体目标 这个开发“opmenta”应用程序是为了增加对 FMO-D/FMOE 功能的机械理解 宿主防御细菌“感染并开发“op nove”方法和模式“生物体的文本，因此 使未来的研究能够阐明 FMO 在 C. e5egans 和哺乳动物先天免疫中的作用和调节 该项目的中心假设是 HLH-CD/TFEB 和 NHR-JK/PPAR-α 诱导表达 FMO-P/FMOQ 通过 FMO-P 活性依赖性抗菌机制进行宿主防御。 sis，我们将定义fmo-P/FMOQ基因调控的上游机制和fmo-P/FMOQ基因调控的下游机制 FMO-D/FMOE 介导的宿主防御由于创新而在技术上具有创新性。 应用新方法测定 C. e5egans 中的过氧化“ipids，以使用合成“etha”- 能够发现特定的和遗传冗余的作用组织，并使用遗传互补 C. e5egans 中重建的古代哺乳动物 FMO 的体内功能“评估”。 所提出的工作在概念上是创新的，它将 HLH-MN/TFEB 与 NHR-ST/PPAR-α 连接起来以调节 FMO-D/FMOE（揭示代谢与先天免疫之间的新联系）及其提议 FMO-D/FMOE 作为感染期间 ROS 和氧化信号“ipids 的来源”的作用。这个建议“很高”y 与人类健康相关，因为它关注人类保守的基因和途径。 Posa”非常重要，因为它直接解决了 FMO 基础知识边缘的重要差距 作为先天免疫效应物的作用和调节此外，试剂、测定、新模式生物体和。 了解“通过这一开发“opmenta”项目获得的优势“开辟了先天免疫研究的新途径” 和 FMO 功能，他为宿主导向疗法的理性设计开辟了道路 细菌“感染和微生物群失调。因此，该建议”与人类健康高度相关，并且 我们期望该项目能够产生重要而广泛的积极影响。