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

• 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
• 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

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.

摘要 脑卒中发病时大脑的发育阶段在损伤中起着关键作用。炎症是一个标志 围产期脑损伤的早期损伤和修复。以前的治疗工作主要集中在 急性保护神经元，但这种策略似乎是短期的。很少有研究关注 开发针对脑血管界面的药物。我们的长期目标是确定有效的 和安全治疗围产期中风，并促进转化为临床实践。新出现的证据 人类婴儿已经提出，n3-多不饱和脂肪酸（n3-PUFA，即，ω-3脂肪酸和 衍生物/代谢物）在正常的出生后脑发育和损伤的脑发育中起重要作用。 新生儿大脑在啮齿类动物中，n3-PUFA在成年中风、感染后的青少年脑中以及 在新生儿脑缺氧缺血后，影响一系列个体炎症机制 和血管效应。我们建议确定是否n3-PUFA发挥有益的影响后，围产期中风 通过中枢机制-通过减弱1-磷酸鞘氨醇（S1 P）/S1 P受体2（S1 PR 2）- 介导的信号在免疫神经血管轴和重组脂质信号。增强 对n3-PUFA介导的在减少脑损伤和/或促进脑修复中的作用的机制理解 患有围产期中风的新生儿几乎可以立即改变受伤的管理， 新生儿，以提高他们的大脑发育和长期的运动和认知成果。示范 S1 P/S1 PR 2信号传导是靶点n3-PUFA将导致识别新的治疗靶点， 围产期中风 我们将通过修改N3-PUFA的表达来检验N3-PUFA增强围产期卒中后脑修复的中心假设。 S1 P/S1 PR 2信号在免疫神经血管轴。 在目标1中，我们将确定膳食n3-PUFA在减轻神经炎症和血管炎中的作用。 在围产期局灶性动脉卒中或感染后的炎症，以及从急性 S1 PR 2信号完整或中断的小鼠新生儿脑损伤。在目标2中，我们将研究长期 饮食n3-PUFA和改变脑脂质组成对脑修复、脑连接和 围产期局灶性动脉卒中后的功能结局。在目标3中，我们将审查短期和长期 卒中后药理学S1 PR 2抑制和n3-PUFA给药对血管重塑的影响， 大脑连接和改善的功能表现。 我们将使用我们发明的一种新的临床相关的围产期局灶性动脉卒中模型， 功能丧失和功能获得的遗传和药理学方法和先进的非 侵入性成像方法，以了解如何靶向免疫神经血管轴，以增强大脑 围产期中风后的修复。检查血管炎症并创建血管炎症图谱的新方法 随着时间的推移，血管重塑和血管-小胶质细胞相互作用在体内，连同脑 连通性措施，将增强对疾病中大脑修复的认识。