Childhood stroke: effects of infection-induced arteriopathies

儿童中风：感染引起的动脉病的影响

基本信息

批准号：
10084326
负责人：
Zinaida S Vexler
金额：
$ 50.51万
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：
2018
资助国家：
美国
起止时间：
2018-04-15 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10084326
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 Structure 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

项目摘要

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.

抽象的中风是儿童死亡原因之一，但受到不成比例的关注。这中风开始时大脑的发育阶段在伤害机制中起关键作用。在人类中，围产期动脉中风很频繁，但几乎永远不会复发，而儿童动脉缺血性中风（CAI）是频繁的频率较低，但其复发率的高度很高。新兴的临床数据表明，大脑动脉炎是强烈预测中风复发，最近的病毒感染使CAIS易于通过敏感脉管系统。假定白细胞通过用作最终来增加CAI的风险及其复发感染引起的大脑动脉疾病的介体。为了了解病毒感染如何加剧CAI，我们通过在产后第18天（P18）小鼠中给药类似于收费的受体3配体Poly-I：C。为了模仿Cais，我们建立了一种新型的适合年龄的儿童中风模型，瞬时脑动脉闭塞（TMCAO）在P21小鼠中。我们假设病毒感染诱导的动脉疾病加剧了髓样细胞中的儿童中风依赖方式。我们将检查p18病毒感染对产生血管炎症的影响，动脉病变和改变白细胞表型（AIM 1），确定抑制任何白细胞募集或中性粒细胞信号传导减弱感染引起的血管炎症和损伤的加重儿童中风（AIM 2），并确定单核细胞VS的作用。中性粒细胞信号传导增强破坏儿童中风后通过感染之前的大脑连通性（AIM 3）。我们将利用几种药理和体内的遗传策略，以破坏信号传导或废除髓样细胞单个子集和使用新颖的工具检查体内的血管重新映射与大脑连通性的变化有关术语功能结果。在感染和/或中风后与少年大脑隔离的血管中，我们将进一步检查血管炎症和内皮激活的模式。记者Lys-EGFP-KI的使用 CCR2介导的单核细胞运输的小鼠和记者小鼠将可视化髓样细胞，将它们与脑免疫细胞区分开，并鉴定表型白细胞变化。纵向多模式MRI将非侵入性描绘中风严重性，复发和出血转化通过病毒感染增强，并描绘了血管结构的变化（MR血管造影）。我们将检查在男性和女性中的影响，因为CAI在男孩中比在女孩中更常见，而先天性的保护作用免疫受体可能是性别依赖性的。我们确定如何改善儿童中风的独特能力在感染触发的动脉疾病之后改变白细胞表型将严重推动了解CAI并确定新的药理学靶标。