Childhood stroke: effects of infection-induced arteriopathies

儿童中风：感染引起的动脉病的影响

• 批准号: 10329941
• 负责人: Zinaida S Vexler
• 金额: $ 50.73万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10329941
• 关键词: 18 year old; Acute; Adolescent; Adult; Affect; Age; Albumins; Angiography; Architecture; Arterial Disorder; Attention; Attenuated; Bacterial Infections; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Injuries; Cause of Death; Cells; Cerebrum; Child; Childhood; Childhood stroke; Clinical Data; Development; Diffusion Magnetic Resonance Imaging; Disease; Encephalitis; Endothelium; Extravasation; Female; Flow Cytometry; Hemorrhage; Histologic; Human; Immune; Immune response; Immunologic Receptors; Individual; Infection; Inflammation; Inflammatory; Injury; Ischemic Stroke; Knock-in Mouse; Knowledge; Lead; Leukocyte Trafficking; Leukocytes; Ligands; Link; Magnetic Resonance Imaging; Mediating; Mediator of activation protein; Microcirculation; Microglia; Middle Cerebral Artery Occlusion; Modeling; Mus; Myelogenous; Myeloid Cells; Outcome; Pattern; Peripheral; Permeability; Pharmacology; Phenotype; Play; Poly I-C; Rattus; Recurrence; Reporter; Rodent Model; Role; Seminal; Severities; Signal Transduction; Stenosis; Stroke; TLR2 gene; TLR3 gene; Therapeutic Effect; Tracer; Vascular Permeabilities; Viral; Virus Diseases; angiogenesis; behavioral outcome; blood-brain barrier permeabilization; boys; cerebral arteriopathy; density; functional outcomes; genetic approach; girls; imaging study; in vivo; male; monocyte; multimodality; myelination; neonatal brain; neonatal mice; neuroinflammation; neurovascular; neutrophil; novel; perinatal ischemic stroke; perinatal stroke; post stroke; postnatal; professor; recruit; sex; stroke model; stroke risk; therapeutic target; tool; trafficking; vascular inflammation; vascular injury

ABSTRACT Stroke is among the top ten causes of death in children but has received disproportionally little attention. The developmental stage of the brain at the stroke onset plays key role in injury mechanisms. In humans, perinatal arterial stroke is frequent but is almost never recurrent, whereas childhood arterial ischemic stroke (CAIS) is less frequent but its recurrence rate is strikingly high. Emerging clinical data show that cerebral arteriopathy is strongly predictive of stroke recurrence and that recent viral infection predisposes to CAIS by sensitizing the vasculature. Leukocytes have been postulated to increase CAIS risk and its recurrence by serving as ultimate mediators of infection-induced cerebral arteriopathies. To understand how viral infection exacerbates CAIS, we established a novel age-appropriate model of childhood arteriopathy induced by viral infection via administration of a Toll-like receptor 3 ligand Poly-I:C in postnatal day 18 (P18) mice. To mimic CAIS, we established a novel age-appropriate childhood stroke model, transient middle cerebral artery occlusion (tMCAO) in P21 mice. We hypothesize that viral infection-induced arteriopathy exacerbates childhood stroke in myeloid cell- dependent manner. We will examine effects of viral infection at P18 in producing vascular inflammation, arteriopathy and changes leukocyte phenotypes (Aim 1), determine if inhibition of either leukocyte recruitment or neutrophil signaling attenuate infection-induced exacerbation of vascular inflammation and injury after childhood stroke (Aim 2), and determine the role of monocyte Vs. neutrophil signaling in enhancing disrupted brain connectivity after childhood stroke by preceding infection (Aim 3). We will utilize several pharmacological and genetic strategies in vivo to disrupt signaling or abolish trafficking of individual subsets of myeloid cells and use novel tools to examine vascular re-mapping in vivo in relation to changes in brain connectivity and long- term functional outcomes. In vessels isolated from juvenile brains following infection and/or stroke, we will further examine vascular inflammation and modes of endothelial activation. The use of reporter Lys-eGFP-ki mice and reporter mice with defective CCR2-mediated monocyte trafficking will enable visualizing myeloid cells, distinguishing them from brain immune cells, and identifying phenotypic leukocyte changes. Longitudinal multi-modal MRI will non-invasively delineate stroke severity, recurrence and hemorrhagic transformation enhanced by viral infection, and delineate changes in vessel architecture (MR angiography). We will examine effects in males and females because CAIS is more common in boys than in girls and protective role of innate immune receptors may be sex-dependent. Our unique ability to identify how to ameliorate childhood stroke by changing the leukocyte phenotypes following infection-triggered arteriopathy would critically advance the understanding of CAIS and identify new pharmacologic targets.

摘要 中风是儿童死亡的十大原因之一，但很少受到关注。的 脑卒中发病时大脑的发育阶段在损伤机制中起着关键作用。在人类中，围产期 动脉中风是常见的，但几乎从来没有复发，而儿童动脉缺血性中风（CAIS）， 但复发率却非常高。新出现的临床数据表明，脑动脉病是 强烈预测卒中复发，近期病毒感染通过使 脉管系统白细胞被认为是增加CAIS风险和复发的最终因素， 感染引起的脑动脉病的介质。为了了解病毒感染如何加重CAIS，我们 建立了一种新的适合年龄的模型，儿童动脉病引起的病毒感染， 在出生后第18天（P18）小鼠中施用Toll样受体3配体Poly-I：C。为了模仿CAIS，我们 建立了一种新的适合年龄的儿童中风模型，短暂性大脑中动脉闭塞 （tMCAO）。 我们假设病毒感染引起的动脉病变加重了儿童期骨髓细胞中风， 依赖的方式。我们将研究病毒感染在P18产生血管炎症的影响， 动脉病变和改变白细胞表型（目的1），确定是否抑制白细胞募集 或中性粒细胞信号转导减弱感染诱导的血管炎症和损伤的恶化， 儿童中风（目的2），并确定单核细胞与中性粒细胞信号转导在增强破坏的作用。 儿童中风后的脑连接与先前的感染（目标3）。我们将使用几种药物 和遗传策略，以破坏信号传导或消除单个骨髓细胞亚群的运输， 使用新的工具来检查体内血管重新映射与大脑连接和长 长期功能性成果。在从感染和/或中风后的幼年脑中分离的血管中，我们将 进一步检查血管炎症和内皮激活模式。报告基因Lys-eGFP-ki的使用 CCR 2介导的单核细胞运输缺陷的小鼠和报告小鼠将能够可视化骨髓 细胞，将它们与脑免疫细胞区分开来，并识别表型白细胞的变化。纵向 多模态MRI将非侵入性地描述卒中的严重程度、复发和出血性转化 通过病毒感染增强，并描绘血管结构的变化（MR血管造影术）。我们将研究 影响男性和女性，因为CAIS在男孩中比在女孩中更常见，先天性的保护作用 免疫受体可能是性别依赖性的。我们独特的能力，以确定如何改善儿童中风， 感染引发的动脉病后白细胞表型的改变， 了解CAIS并确定新的药理学靶点。

项目成果

CD36 neutralisation blunts TLR2-IRF7 but not IRF3 pathway in neonatal mouse brain and immature human microglia following innate immune challenge.

• DOI: 10.1038/s41598-023-29423-0
• 发表时间: 2023-02-09
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Gadagkar, Shruti Gururaj;Lalancette-Hebert, Melanie;Thammisetty, Sai Sampath;Vexler, Zinaida S.;Kriz, Jasna
• 通讯作者: Kriz, Jasna