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.

含氟氨基酸的单加氧酶（FMOs）是一种保守的氧化有机分子的酶。 Cu“es，如外源性物质，并通过pasma膜转运蛋白促进它们的输出。我们最近发现- 认为FMO是重要的先天宿主防御效应器。这个项目使用了体内还原论的方法 以小杆线虫为模式生物， FMO。这个项目的“长期果阿”是理解C。e5 egans和mamma“ian fmo是regu- 以及它们如何在感染期间促进宿主防御。我们先前的研究支持C. e5e- Gans FMO-D、人FMOE和其它FMOs在宿主-微生物中可能具有进化保守的功能 交互.这些功能是什么以及它们是如何调节的目前还不清楚。这是一个重要 fundamenta”知道“边缘差距，阻碍了对动物体内平衡和宿主防御的理解， 这使治疗感染或炎症性疾病的治疗机会变得模糊。总体目标是 这一开发的目的是增加对FMO-D/FMOE功能的机械理解， 本文介绍了宿主对细菌感染的防御和开发“新”方法和模式”生物体，从而 为今后的研究奠定基础，以阐明FMOs在C. e5egans and mamma“ian innate im- 社区本项目的中心假设是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用于宿主防御5。为了测试这个假设- 因此，我们将明确fmo-P/FMOQ基因调控上游机制和下游机制， FMO-D/FMOE介导的宿主防御。本研究的创新之处在于技术创新 应用新的方法测定C. e5 egans，用于合成“etha”- 发现特定的和遗传学上冗余的作用组织的能力，以及使用遗传补偿， 重组古乳腺FMOs体内功能”伊娃“评价e5egans。此外，亲- 提出的工作是概念上的创新，将HLH-MN/TFEB与NHR-ST/PPAR-α联系起来， FMO-D/FMOE（揭示了代谢和先天免疫之间的新联系）及其提出的 FMO-D/FMOE在感染过程中作为ROS和氧化信号脂的来源。这个提议”太高“了 因为它关注的是人类中保守的基因和途径。这个亲- posa”是高度重要的，因为它直接解决了FMO的基础”知道“边缘的重要差距 作为先天免疫效应子的作用和调节。此外，试剂、测定法、新模式”生物体“和 通过这个开发项目获得的优势将为先天免疫研究开辟新的途径 和FMO功能和他“p创造了一个前进的道路的理性”设计的主机定向治疗， 细菌感染和微生物群失调。因此，这一建议对人类健康来说是“高度”的， 我们期望该项目将产生重要和广泛的积极影响。