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.

摘要 据估计，10%的美国孕妇报告在过去30天内饮酒，3%的孕妇报告在过去30天内饮酒。 报告酗酒。产前酒精暴露（PAE）会导致人类严重的认知障碍， 在动物模型中，持续的PAE诱导的神经炎症可能导致这些损伤， 尽管潜在的机制还没有被很好地理解。了解这些机制将有助于 可以改善这些人的结果的策略。 神经炎症是通过脂质介质、细胞因子和细胞因子的复杂和动态网络诱导的。 趋化因子由各种神经免疫细胞产生，包括小胶质细胞， 大脑中类似巨噬细胞的先天免疫细胞。它们是先天免疫的第一线， 免疫调节和炎症消退。多不饱和脂肪酸（PUFA）提供关键的 结构和功能成分在大脑和常驻免疫细胞。长链多不饱和脂肪酸可以引起 通过其代谢物的免疫调节作用;这些脂质介质可以改变免疫调节的强度和/或持续时间。 炎症欧米茄-3多不饱和脂肪酸是众所周知的，其抗炎和促进解决的性质; 相关的脂质代谢物包括衍生自二十碳五烯酸（EPA）的E-系列消退素， 通过结合chemerin受体（ChemR23）的抗炎作用。小胶质细胞中EPA含量很高 和ChemR23。ChemR23的激活抑制神经炎症，而其去除增加 炎症怀孕期间饮酒与胎儿中PUFA积累减少有关。 这可能会破坏小胶质细胞解决神经炎症的能力。的长期目标 所提出的研究是评估消退素在PAE诱导的神经炎症中的作用。具体地说，这 研究将利用ChemR23敲除（KO）小鼠品系。怀孕的老鼠会接触酒精， 提供富含EPA的饮食。将评估后代脑中的脂质和消退素浓度 (Aim 1）和神经炎症（目的2）在断奶。实验将在KO和背景中进行 （C57BL/B6J）小鼠中进行，以在功能上测试EPA衍生的消退素在PAE诱导的神经炎症中的作用。 查佩尔山营养研究所（NRI）位于北卡罗来纳州研究园区 （NCRC）。校园保持着多所大学，公司和 社区合作伙伴，并提供最先进的实验室和动物设施，容纳所有必要的设备， 拟议的研究。我的导师桑德拉·穆尼博士在PAE获得了丰厚的奖学金， 神经发育，行为研究，granimetry，和学术合作。在一起，博士。 穆尼的指导和NRI将帮助我实现我的目标;加强我在PAE的背景， 营养，神经发育和神经免疫学研究，建立一个强大的神经发育和 神经免疫学评估技能，并加强我的科学写作和语法技能。