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

摘要 据估计，美国10%的孕妇报告在过去30天内饮酒，3%的孕妇报告在过去30天内饮酒 报告酗酒事件。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有助于这些损害， 尽管潜在的机制还不是很清楚。了解这些机制将有助于 可能会改善这些人的结果的战略。 神经炎症是通过复杂而动态的脂质介质、细胞因子和 趋化因子由各种神经免疫细胞产生，包括常驻的小胶质细胞 脑内类似巨噬细胞的先天免疫细胞。它们是先天免疫的第一道防线， 免疫调节和消退炎症。多不饱和脂肪酸(PUFA)提供关键的 大脑和居民免疫细胞中的结构和功能成分。长链多不饱和脂肪酸可引发 通过其代谢物的免疫调节作用；这些脂质介体可以改变 发炎。Omega-3多不饱和脂肪酸以其抗炎和促进分解的特性而闻名； 相关的脂质代谢物包括来自二十碳五烯酸(EPA)的E系列分解素，它可以诱导他们的 通过与趋化蛋白受体(ChemR23)结合而发挥抗炎作用。小胶质细胞有高水平的EPA 和ChemR23。ChemR23的激活抑制神经炎症，而其清除增加 发炎。怀孕期间饮酒与体内多不饱和脂肪酸积累减少有关 发育中的大脑，可能破坏小胶质细胞分解神经炎症的能力。的长期目标是 这项拟议的研究旨在评估溶血素在PAE诱导的神经炎症中的作用。具体地说，这 这项研究将利用ChemR23基因敲除(KO)小鼠品系。怀孕的小鼠将暴露在酒精和 提供了一种富含EPA的饮食。后代将被评估大脑中的脂质和解析素浓度 (目标1)和神经炎症(目标2)断奶。实验将在KO和背景中进行 (C57BL/B6J)小鼠，从功能上测试EPA衍生的解决素在PAE诱导的神经炎症中的作用。 北卡罗来纳州教堂山大学营养研究所(NRI)位于北卡罗来纳州研究校园 (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 建议的研究。我的导师桑德拉·穆尼博士在PAE获得了很高的奖学金， 神经发展、行为研究、勇气和学术合作。综上所述，戴维斯博士说。 穆尼的指导和NRI将帮助我实现以下目标：加强我在PAE的背景， 营养、神经发育和神经免疫学研究，构筑强大的神经发育和 神经免疫学评估技能套装，并加强我的科学写作和手腕技能。

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.