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具有双重作用—— 如果再灌注较早，则具有神经保护作用，但如果再灌注，则出现不良事件并增加神经功能障碍 机械血栓切除术彻底改变了成人中风的护理，并且已被证明有益于治疗。 多项随机临床试验，时间窗逐渐从 4.5 小时增加到 24 小时或更长。 患有动脉缺血性中风的儿童，回顾性病例系列表明安全性和可能的​​益处 然而，选择偏倚和缺乏未经治疗的对照结果引起了人们对血栓切除术是否存在担忧 儿童可以安全地从血管内血栓切除术中受益目前缺乏科学证据。 小儿缺血性中风（PAIS）后何时可以安全地去除血栓。 和儿童动脉缺血性中风（CAIS）是具有不同发生率和复发率的疾病， 由于中枢神经系统成熟度的年龄相关差异，许多非重叠损伤机制 在这项探索性 R21 资助中，我们将开始填补知识空白。 使用实验性 PAIS 和 CAIS 模型可以安全地去除血栓。 中心假设：单核细胞-小胶质细胞-中性粒细胞相互作用介导不同的时间窗 PAIS 和 CAIS 晚期再通的不利影响。 在长期短暂大脑中动脉闭塞（tMCAO）后的“晚期再灌注”模型中 对于新生儿和青少年男性和女性，我们将确认再灌注并检查出血程度 与血脑屏障（BBB）完整性、水肿和短期组织学结果相关的转化。 每个年龄组炎症反应的严重程度将由炎症反应的积累决定 血液和大脑中的炎性细胞因子/趋化因子（多重）、出血标记物（d-二聚体） 分析）以及浸润的中性粒细胞和单核细胞的表型（流式细胞术）（目标 1）。 检查 CCR2 或 Cx3CR1 信号传导的基因破坏是否会影响出血的严重程度 转化、血脑屏障渗漏以及晚期再灌注后的短期组织学和功能结果 在两种性别的 P9 和 P21 小鼠中进行实验，并确定大脑成熟对浸润表型的作用 白细胞和活化的小胶质细胞/巨噬细胞（流式细胞术、免疫荧光）和 神经炎症（细胞因子多重）（目标 2）。 定义出生后大脑成熟如何影响晚期出血性转化的易感性 血管再通，并帮助为患有此病的儿童的婴儿制定延迟血管再通的安全指南 中风。