Woods Hole Center for Oceans and Human Health

伍兹霍尔海洋与人类健康中心

• 批准号: 10225184
• 负责人: JOHN J STEGEMAN
• 金额: $ 3.07万
• 依托单位: WOODS HOLE OCEANOGRAPHIC INSTITUTION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225184
• 关键词: Address; Adolescent; Adult; Affect; Animal Model; Award; Axon; Behavior; Behavioral; Behavioral Assay; Brain; Cells; Defect; Development; Elderly; Embryo; Engineering; Exposure to; Fishes; Fluorescence-Activated Cell Sorting; Functional disorder; Gene Expression; Gene Expression Profile; Health; Histologic; Human; Immune; Inflammation; Inflammatory; Ion Channel; Joints; Lead; Learning; Life; Mediating; Microglia; Molecular; Morphology; Nerve Degeneration; Nervous system structure; Neuraxis; Neuroglia; Neurons; Neurotransmitter Receptor; Oceanography; Oceans; Parents; Play; Predisposition; Research; Research Project Summaries; Research Training; Rest; Risk; Role; Saxitoxin; Secondary to; Signal Transduction; Sodium Channel; Structure; Testing; Toxin; Transgenic Organisms; Up-Regulation; Wood material; Zebrafish; axon growth; career development; cell mediated immune response; cell type; classical conditioning; confocal imaging; developmental neurotoxicity; developmental toxicity; doctoral student; domoic acid; early life exposure; environmental chemical; experimental study; exposed human population; harmful algal blooms; imaging genetics; insight; myelination; neurobehavior; neurobehavioral; neurodevelopment; neuroinflammation; neuronal survival; neurotoxicity; oligodendrocyte lineage; prenatal; programs; response; stressor; transcriptome sequencing; voltage

Project Summary The research proposed in this supplement tests the hypothesis that developmental domoic acid (DA) exposure affects microglia, the resident immune cells in the brain, resulting in altered function, impacts on neuron health, and neurobehavioral deficits. Microglia play an important role in inflammation and responding to immune challenge in the brain. Microglial dysfunction in development can be caused by exposure to environmental chemicals and can lead to changes in brain structure, function, and neurobehavior. Early life impacts on microglia can have far-reaching impacts, including increased sensitivity to subsequent stressors causing elevated neuroinflammation and eventual neurodegeneration. Despite the importance of this cell type, very little is known about the role of microglia in mediating the effects of harmful algal toxins, including DA. The proposed research will investigate the impacts of developmental DA on microglial activation and assess the impacts of early life inflammation on neuronal survival and learning. In specific aim 1, we test the hypothesis that developmental DA exposure causes microglial activation in zebrafish brain. We will utilize confocal imaging and transgenic zebrafish expressing cell-specific fluorescent markers to assess changes in microglial morphology indicative of activation. This study will also identify windows of susceptibility. In specific aim 2, we will investigate the impacts of developmental exposure on sensitivity to later life insults. We will test the hypothesis that developmental exposure to DA will cause increased inflammation and neurodegeneration, as well as neurobehavioral changes, in response to exposure in adult fish. This aim will utilize well-characterized behavioral assays of associative learning and histological markers of neuroinflammation and neurodegeneration. In specific aim 3, we will test the hypothesis that developmental DA exposure causes altered gene expression and upregulation of inflammatory factors in microglia. We will characterize the microglia-specific transcriptional profiles associated with DA exposure using fluorescence-activated cell sorting followed by RNA sequencing. The results from the proposed study will provide important information about the role of microglia as a potential target of domoic acid, and the risks of developmental exposure.

项目概要 本补充品中提出的研究测试了发育软骨藻酸 (DA) 的假设 暴露会影响小胶质细胞，即大脑中常驻的免疫细胞，导致功能改变， 对神经元健康和神经行为缺陷的影响。小胶质细胞在以下方面发挥着重要作用 炎症和对大脑免疫挑战的反应。发育中的小胶质细胞功能障碍 可能是由于接触环境化学物质引起的，并可能导致大脑结构的变化， 功能和神经行为。生命早期对小胶质细胞的影响可能会产生深远的影响，包括 对随后的压力源的敏感性增加，导致神经炎症加剧，最终 神经变性。尽管这种细胞类型很重要，但人们对它的作用知之甚少。 小胶质细胞介导有害藻类毒素（包括 DA）的影响。拟议的研究将 研究发育 DA 对小胶质细胞激活的影响并评估早期 生活炎症对神经元存活和学习的影响。在具体目标 1 中，我们检验以下假设： 发育阶段的 DA 暴露会导致斑马鱼大脑中的小胶质细胞激活。我们将利用共焦 成像和表达细胞特异性荧光标记的转基因斑马鱼以评估 小胶质细胞形态表明激活。这项研究还将确定易感性窗口。在 具体目标2，我们将研究发育暴露对以后生活敏感性的影响 侮辱。我们将检验以下假设：发育时期接触 DA 会导致增加 炎症和神经退行性变以及神经行为变化，以响应暴露 成年鱼。这一目标将利用联想学习和 神经炎症和神经变性的组织学标志物。在具体目标 3 中，我们将测试 假设发育期 DA 暴露会导致基因表达改变和基因表达上调 小胶质细胞中的炎症因子。我们将表征小胶质细胞特异性转录谱 使用荧光激活细胞分选和随后的 RNA 测序与 DA 暴露相关。 拟议研究的结果将提供有关小胶质细胞作为神经细胞的作用的重要信息。 软骨藻酸的潜在目标，以及发育暴露的风险。