Hemorrhagic transformation associated with delayed reperfusion in perinatal and childhood ischemic stroke: brain maturation-dependent role of leukocytes

与围产期和儿童缺血性卒中延迟再灌注相关的出血性转化：白细胞的脑成熟依赖性作用

• 批准号: 10811475
• 负责人: Zinaida S Vexler
• 金额: $ 44.41万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10811475
• 关键词: Acute; Adolescent; Adult; Adverse effects; Adverse event; Affect; Age; Beds; Biological Assay; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Caring; Case Series; Cerebral hemisphere hemorrhage; Cerebrum; Child; Childhood; Childhood stroke; Consensus; Development; Diet; Disease; Disputes; Edema; Extravasation; Family; Female; Fibrin fragment D; Flow Cytometry; Functional disorder; Genetic; Goals; Grant; Hemorrhage; Histologic; Hour; Immune; Immune system; Immunofluorescence Immunologic; Infant; Inflammation; Inflammatory; Inflammatory Response; Injury; International; Intervention; Ischemic Stroke; Knowledge; Lactation; Late Effects; Leucocytic infiltrate; Leukocytes; Lipids; Macrophage; Malignant - descriptor; Mechanics; Mediating; Mesenchymal Stem Cells; Microcirculation; Microglia; Middle Cerebral Artery Occlusion; Modeling; Mus; Neonatal; Neonatal Brain Injury; Neurologic; Neutrophil Infiltration; Omega-3 Fatty Acids; Outcome; Perinatal; Phenotype; Play; Predisposition; Pregnancy; Rattus; Recurrence; Reperfusion Injury; Reperfusion Therapy; Risk; Rodent; Role; Safety; Science; Selection Bias; Signal Transduction; Societies; Stroke; Structure of choroid plexus; Therapeutic; Thrombectomy; Thrombus; Time; Viral; Work; age group; age related; blood-brain barrier permeabilization; cerebral arteriopathy; cerebral artery; chemokine; clinically relevant; cost; cytokine; disability; endovascular thrombectomy; evidence base; experimental study; extracellular vesicles; functional outcomes; infant brain injury; male; meetings; monocyte; mouse model; neuroinflammation; neuroprotection; neurovascular; neutrophil; novel; perinatal ischemic stroke; post stroke; postnatal; randomized, clinical trials; repaired; response; response to injury; sex; stroke model; therapeutically effective; timeline

Abstract Reperfusion of cerebral microcirculation following cerebral artery blockage can have dual roles — neuroprotection if reperfusion is early but adverse events and increased neurological disability if reperfusion is delayed. Mechanical thrombectomy has revolutionized care in adult stroke and is of proven benefit in multiple randomized clinical trials with time windows gradually increasing from 4.5 to 24 or more hours. In children with arterial ischemic stroke, retrospective case series suggest safety and possible benefit of thrombectomy, however selection bias and a lack of non-treated control outcomes raise concerns on whether children can safely benefit from endovascular thrombectomy. There is lack of science-based evidence on when it is safe to remove thrombus after pediatric ischemic stroke. Perinatal arterial ischemic stroke (PAIS) and childhood arterial ischemic stroke (CAIS) are diseases with distinct occurrence and recurrence rates and many non-overlapping injury mechanisms due to the age-related differences in the maturation of the CNS and the immune system. In this exploratory R21 grant we will begin filling the knowledge gap of when it is safe to remove thrombus using experimental PAIS and CAIS models. Central Hypothesis: Monocyte-microglia-neutrophil interactions mediate distinct time windows for adverse effects of late recanalization in PAIS and CAIS. In models of ‘late reperfusion’ following long transient middle cerebral artery occlusion (tMCAO) in neonatal and juvenile males and females we will confirm reperfusion and examine the extent of hemorrhagic transformation in relation to blood-brain barrier (BBB) integrity, edema and short-term histological outcomes. The magnitude of the inflammatory response in each age group will be determined by accumulation of inflammatory cytokines/chemokines (multiplex) in the blood and in the brain, hemorrhagic markers (d-dimer assay) and the phenotypes of infiltrated neutrophils and monocytes (flow cytometry) (Aim 1). We will then examine whether genetic disruption of CCR2 or Cx3CR1 signaling affects the magnitude of hemorrhagic transformation, BBB leakage, and short-term histological and functional outcomes following late reperfusion in P9 and P21 mice of both sexes, and determine the role of brain maturation on the phenotypes of infiltrated leukocytes and activated microglia/macrophages (flow cytometry, immunofluorescence) and neuroinflammation (cytokine multiplex) (Aim 2). The proposed studies will serve as proof-of-principle in defining how postnatal brain maturation affects the susceptibility to hemorrhagic transformation after late recanalization and help define safety guidance for delayed recanalization in infants of children who suffer stroke.

抽象的 脑动脉阻塞后脑微循环的再灌注可能具有双重作用 - 神经保护如果再灌注早期，但不良事件并增加神经疾病，如果再灌注 延迟。机械血栓切除术已彻底改变了成人中风的护理，并且在 随机窗口的多个随机临床试验逐渐从4.5逐渐增加到24个小时。在 具有动脉缺血性中风的儿童，回顾性病例系列提出了安全性和可能的​​好处 血栓切除术，但是选择偏见和缺乏未经处理的控制结果引起了人们对是否是否是否担心 儿童可以安全地从血管内血栓切除术中受益。缺乏基于科学的证据 小儿缺血性中风后可以安全去除血栓时。围产期动脉缺血性中风（PAIS） 儿童动脉缺血性中风（CAI）是具有明显发生和复发率的疾病， 由于CNS的成熟年龄差异，许多非重叠的伤害机制 和免疫系统。在此探索性R21赠款中，我们将开始填补何时的知识差距 可以使用实验性的PAIS和CAIS模型可以安全去除血栓。 中央假设：单核细胞 - 神经元 - 中性亲子相互作用媒体不同的时间窗口 PAIS和CAI的晚期再通化的不利影响。 在较长的短暂瞬时脑动脉闭塞（TMCAO）之后的“晚期再灌注”模型中 新生儿和少年男性和女性我们将确认再灌注并检查出血的程度 与血脑屏障（BBB）完整性，水肿和短期组织学结果有关的转化。 每个年龄段的炎症反应的大小将通过积累来确定 血液和大脑中的炎症细胞因子/趋化因子（多重），出血标记（D-二二聚体 测定）以及浸润的中性粒细胞和单核细胞（流式细胞仪）的表型（AIM 1）。然后我们会 检查CCR2或CX3CR1信号的遗传破坏是否会影响出血的大小 转化，BBB泄漏以及后期再灌注后的短期组织学和功能结果 在两性的P9和P21小鼠中，并确定大脑成熟在浸润表型中的作用 白细胞和活化的小胶质细胞/巨噬细胞（流式细胞仪，免疫荧光）和 神经炎症（细胞因子多重）（AIM 2）。拟议的研究将作为原则证明 定义产后大脑的成熟如何影响迟到后出血转化的敏感性 重新定制并有助于定义安全指南，以延迟遭受的儿童的延迟再通电 中风。