Perinatal stroke: effects of bioactive lipids on immune-neurovascular axis and brain repair

围产期中风：生物活性脂质对免疫神经血管轴和脑修复的影响

基本信息

批准号：
10064968
负责人：
Zinaida S Vexler
金额：
$ 49.97万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-18 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10064968
关键词：
Acute Adolescent Adult Affect Aftercare Age Anisotropy Atlases Attenuated Blood Blood - brain barrier anatomy Blood Vessels Brain Brain Injuries Cells Cerebrum Chronic Cognitive Connective Tissue Development Diet Disease Endothelial Cells Endothelium Exposure to Extracellular Matrix Extracellular Matrix Degradation Family Female Functional disorder Generations Genetic Goals Histologic Human Immune Immune Targeting Individual Infant Infection Inflammation Inflammatory Inflammatory Response Injury Ischemic Stroke Leukocytes Life Lipids Live Birth Long-Term Effects Maps Measures Mediating Methodology Microcirculation Microglia Middle Cerebral Artery Occlusion Modeling Motor Mus Myeloid Cells Neonatal Brain Injury Neuroglia Neurons Newborn Infant Omega-3 Fatty Acids Outcome Performance Perfusion Perinatal Perinatal Brain Injury Perinatal Infection Permeability Pharmacology Phase Phenotype Play Polyunsaturated Fatty Acids Pregnancy Rattus Reperfusion Therapy Rodent Rodent Model Role Signal Transduction Societies Sphingosine-1-Phosphate Receptor Stimulus Stroke Structure Supplementation Term Birth Testing Therapeutic Therapeutic Effect Time Translations Vascular remodeling Work angiogenesis behavioral outcome brain repair cerebrovascular clinical practice clinically relevant cost dietary disability functional outcomes gain of function improved in vivo inhibitor/antagonist injured injury and repair loss of function male myelination neonatal brain neonatal hypoxic-ischemic brain injury neuroinflammation neurovascular new therapeutic target newborn brain injury non-invasive imaging novel novel strategies perinatal ischemic stroke perinatal stroke post stroke postnatal pup repaired response sphingosine 1-phosphate stroke model targeted agent trafficking vascular inflammation vasogenic edema young adult

项目摘要

ABSTRACT The developmental stage of the brain at the stroke onset plays key role in injury. Inflammation is a hallmark of perinatal brain injury, both early injury and repair. Previous therapeutic efforts were mostly focused on protecting neurons acutely, but such strategies appeared to be short-range. Very few studies focused on the development of agents that target cerebrovascular interface. Our long-term goal is to identify effective and safe therapy for perinatal stroke and facilitate translation into clinical practice. Emerging evidence in human infants has suggested that n3-Polyunsaturated Fatty Acids (n3-PUFA, i.e., Omega-3 fatty acids and derivatives/metabolites) play an important role in both normal postnatal brain development and in injured newborn brain. In rodents, n3-PUFA are shown protective in adult stroke, in juvenile brain after infection and in neonatal brain after neonatal hypoxia-ischemia, affecting an array of individual inflammatory mechanisms and vascular effects. We propose to identify whether n3-PUFA exert beneficial effects after perinatal stroke by a central mechanism¬—by attenuating sphingosine-1-phosphate (S1P)/S1P receptor 2 (S1PR2)- mediated signaling at the immune-neurovascular axis and reorganizing lipid signaling. Enhanced mechanistic understanding of n3-PUFA-mediated effects in reducing injury and/or facilitating brain repair in newborns who suffer perinatal stroke would allow for almost immediate changes in management of injured newborns to enhance their brain development and long-term motor and cognitive outcomes. Demonstration that S1P/S1PR2 signaling is the target n3-PUFA will lead to identification of new therapeutic targets for perinatal stroke. We will test the central hypothesis that n3-PUFA enhance brain repair after perinatal stroke by modifying S1P/S1PR2 signaling at the immune-neurovascular axis. In Aim 1, we will determine effects of dietary n3-PUFA in attenuating neuroinflammation and vascular inflammation after perinatal focal arterial stroke or infection, and in microvessels isolated from acutely injured neonatal brain in mice with intact or disrupted S1PR2 signaling. In Aim 2, we will examine long-term effects of dietary n3-PUFA, and of altered brain lipid composition, on brain repair, brain connectivity and functional outcomes after perinatal focal arterial stroke. In Aim 3, we will examine short-term and long-term effects of post-stroke pharmacologic S1PR2 inhibition and n3-PUFA administration on vascular remodeling, brain connectivity and improved functional performance. We will use a novel clinically relevant perinatal focal arterial stroke model that we invented, in conjunction with loss-of-function and gain-of function genetic and pharmacological approaches and advanced non- invasive imaging methodologies, to understand how to target immune-neurovascular axis to enhance brain repair after perinatal stroke. Novel approaches to examine vascular inflammation and create atlas of the remodeling vasculature and of vessel-microglial interactions in vivo over time, together with brain connectivity measures, will enhance the understanding of brain repair in the disease.

抽象的中风开始时大脑的发育阶段在伤害中起关键作用。炎症是一个标志围产期脑损伤，包括早期损伤和修复。以前的治疗工作主要集中在敏锐地保护神经元，但这种策略似乎是短期的。很少有研究重点靶向脑血管界面的药物的发展。我们的长期目标是确定有效和安全疗法用于围产期中风，并促进转化为临床实践。新兴的证据人类婴儿已经提出N3-饱和脂肪酸（N3-PUFA，即omega-3脂肪酸和衍生物/代谢产物）在正常的产后大脑发育和受伤中都起着重要作用新生大脑。在啮齿类在新生儿缺氧 - 缺血性的新生儿大脑中，影响了一系列个体炎症机制和血管效应。我们建议确定N3-PUFA是否在围产期中风后发挥有益的作用通过一种中心机制 - 通过衰减鞘氨醇1-磷酸（S1P）/S1P受体2（S1PR2） - 免疫 - 神经血管轴的介导信号传导并重组脂质信号。增强对N3-PUFA介导的效果的机械理解在减少损伤和/或支持大脑修复方面的作用遭受围产期中风的新生儿将几乎立即改变受伤的管理新生儿可以增强他们的大脑发育以及长期运动和认知结果。示范 S1P/S1PR2信号传导是目标N3-PUFA将导致确定新的治疗靶标围产期中风。我们将测试中心假设，即N3-PUFA通过修改会增强围产期中风后的脑修复免疫神经血管轴的S1P/S1PR2信号传导。在AIM 1中，我们将确定饮食N3-PUFA在衰减神经炎症和血管的影响围产期局灶性助图或感染后的炎症，从急性分离的微血管中在AIM 2中，我们将检查长期饮食N3-PUFA和脑脂质组成改变的影响，对脑修复，脑连接性和围产期局灶性人工伪像中风后的功能结果。在AIM 3中，我们将研究短期和长期冲程后药物学S1PR2抑制和N3-PUFA给药对血管重塑的影响，大脑连通性和功能性能的提高。我们将使用我们发明的新型临床相关围产期局部动脉中风模型通过功能丧失和功能获得的遗传和药物方法以及晚期非 - 侵入性成像方法，了解如何靶向免疫 - 神经血管轴以增强大脑围产期中风后修复。研究血管感染并创建的地图集的新方法随着时间的流逝，体内的重塑脉管系统和血管形成 - 微神经相互作用与大脑一起连通性措施将增强对疾病大脑修复的理解。