Omega-3 supplementation as a therapeutic agent in PAE-induced neuroinflammation

补充 Omega-3 作为 PAE 诱导的神经炎症的治疗剂

• 批准号: 10387762
• 负责人: Kathleen Rose Walter
• 金额: $ 7.21万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10387762
• 关键词: Address; Affect; Age; Alcohol consumption; Alcohols; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Attenuated; Behavioral; Binding; Brain; CMKLR1 gene; Cells; Cognitive; Collaborations; Communities; Complex; Development; Dextrins; Diet; Dietary Supplementation; Eicosapentaenoic Acid; Enzyme-Linked Immunosorbent Assay; Equipment; Excision; Female; Fetal Alcohol Exposure; Fetal alcohol effects; Flow Cytometry; Genes; Goals; Housing; Human; Immune; Impaired cognition; Impairment; Individual; Inflammation; Inflammatory; Intervention; Knock-out; Knockout Mice; Knowledge; Lactation; Link; Lipids; Maltose; Mass Fragmentography; Mediating; Mediator of activation protein; Mentors; Mentorship; Microglia; Morphology; Mouse Strains; Mus; Natural Immunity; Neuroimmune; North Carolina; Nutrient; Nutritional Study; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Phenotype; Play; Polyunsaturated Fatty Acids; Pregnant Women; Production; Property; Reporting; Research; Research Institute; Resolution; Role; Scholarship; Series; Signal Transduction; Supplementation; Testing; Therapeutic Agents; Universities; Weaning; Writing; alcohol consumption during pregnancy; alcohol exposure; animal facility; base; behavioral study; binge drinking; brain cell; chemokine; collaborative environment; cytokine; dietary; experimental study; fatty acid supplementation; immunoregulation; improved outcome; lipid mediator; liquid chromatography mass spectrometry; macrophage; male; mother nutrition; mouse model; neurodevelopment; neuroimmunology; neuroinflammation; novel; nutrition; offspring; postnatal; pre-clinical; pregnant; receptor; skills; treatment strategy

Abstract An estimated 10% of pregnant women in the US report consuming alcohol within the past 30 days, and 3% report binge drinking. Prenatal alcohol exposure (PAE) causes significant cognitive impairment in humans and in animal models, and persistent PAE-induced neuroinflammation may contribute to these impairments, although underlying mechanisms are not well understood. Understanding these mechanisms will inform strategies that may improve outcomes for these individuals. Neuroinflammation is induced through a complex and dynamic network of lipid mediators, cytokines, and chemokines produced from various neuroimmune cells, including microglia which are the resident macrophage-like innate immune cells of the brain. They are the first line of innate immunity and mediate immune regulation and resolution of inflammation. Polyunsaturated fatty acids (PUFAs) provide critical structural and functional components in the brain and in resident immune cells. Long-chain PUFAs can elicit immunomodulatory effects via their metabolites; these lipid mediators can alter the intensity and/or duration of inflammation. Omega-3 PUFAs are well known for their anti-inflammatory and pro-resolving properties; relevant lipid metabolites include E-series resolvins derived from eicosapentaenoic acid (EPA) that elicit their anti-inflammatory effects by binding to the chemerin receptor (ChemR23). Microglia have high levels of EPA and ChemR23. Activation of ChemR23 suppresses neuroinflammation, while its removal increases inflammation. Alcohol consumption during pregnancy is associated with decreased PUFA accumulation in the developing brain which may disrupt the ability of microglia to resolve neuroinflammation. The long-term goal of the proposed research is to evaluate the role of resolvins in PAE-induced neuroinflammation. Specifically, this study will utilize a ChemR23 knockout (KO) mouse strain. Pregnant mice will be exposed to alcohol and provided an EPA-enriched diet. Offspring will be assessed for lipid and resolvin concentrations in the brain (Aim 1) and neuroinflammation (Aim 2) at weaning. Experiments will be done in KO and background (C57BL/B6J) mice to functionally test the role of EPA-derived resolvins in PAE-induced neuroinflammation. The Nutrition Research Institute of UNC Chapel Hill (NRI) is located on the North Carolina Research Campus (NCRC). The campus maintains a collaborative atmosphere among multiple universities, companies and community partners and provides state-of-the-art lab and animal facilities housing all necessary equipment for the proposed research. My mentor Dr. Sandra Mooney sustains a strong scholarship in PAE, neurodevelopment, behavioral studies, grantsmanship, and academic collaboration. Taken together, Dr. Mooney’s mentorship and the NRI will help me to achieve my goals of; strengthening my background in PAE, nutrition, neurodevelopment and neuroimmunology research, build a strong neurodevelopment and neuroimmunology assessment skill set, and strengthen my scientific writing and grantsmanship skills.

抽象的 估计美国有10％的孕妇报告说，过去30天内喝酒，3％ 报告Benge喝酒。产前酒精暴露（PAE）在人类和 在动物模型中，持续的PAE诱导的神经炎症可能会导致这些障碍， 尽管基本机制尚不清楚。了解这些机制将告知 可以改善这些人结果的策略。 神经炎症是通过脂质介质，细胞因子和 来自各种神经免疫细胞产生的趋化因子，包括小胶质细胞 大脑的巨噬细胞样的先天免疫力。它们是先天免疫的第一线和调解 免疫调节和炎症的分辨率。多不饱和脂肪酸（PUFAS）提供关键 大脑和常驻免疫细胞中的结构和功能成分。长链PUFA可以引起 免疫调节作用通过其代谢产物；这些脂质介体可以改变强度和/或持续时间 炎。 Omega-3 Pufas以其抗炎和促进特性而闻名。 相关的脂质代谢产物包括源自eicosapentaenoic酸（EPA）的电子系列分辨素，它们引起了它们 通过与化学蛋白受体结合（ChemR23）来抗炎作用。小胶质细胞具有高水平的EPA 和ChemR23。 ChemR23的激活抑制神经炎症，而其去除量增加 炎。怀孕期间的饮酒与PUFA的积累减少有关 发展大脑，可能破坏小胶质细胞解决神经炎症的能力。长期目标 拟议的研究是评估Resolvevins在PAE诱导的神经炎症中的作用。具体来说，这是 研究将利用ChemR23敲除（KO）小鼠菌株。怀孕的小鼠将暴露于酒精和 提供了富含EPA的饮食。后代将评估大脑中的脂质和分辨浓度 （AIM 1）和神经炎症（AIM 2）在断奶中。实验将在KO和背景中进行 （C57BL/B6J）小鼠在功能上测试EPA衍生的分辨率在PAE诱导的神经炎症中的作用。 UNC教堂山（NRI）营养研究所位于北卡罗来纳州研究校园 （NCRC）。校园在多个大学，公司和 社区合作伙伴并提供最先进的实验室和动物设施，为所有必要的设备提供 拟议的研究。我的心理桑德拉·穆尼（Sandra Mooney）博士在PAE中获得了强大的奖学金 神经发育，行为研究，授予技巧和学术合作。总的来说，博士 Mooney的心态和NRI将帮助我实现自己的目标；加强我的背景， 营养，神经发育和神经免疫学研究，建立强大的神经发育和 神经免疫学评估技能集，并增强了我的科学写作和授予技巧。