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 中风是儿童死亡的前十大原因之一，但却很少受到关注。这个 卒中发病时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，但几乎不会复发，而儿童动脉缺血性中风(Cais)则是。 发病率较低，但复发率高得惊人。不断涌现的临床资料表明，脑动脉病是 中风复发的强烈预测，以及最近的病毒感染通过使 脉管系统。据推测，白细胞作为终极细胞可增加CAIS的风险及其复发。 感染性脑动脉病变的介体。为了了解病毒感染如何加剧CAI，我们 建立一种新的适合儿童年龄的病毒感染所致动脉病变模型 Toll样受体3配体Poly-I：C在出生后第18天(P18)小鼠中的应用。为了模仿cai，我们 建立一种新的适合年龄的儿童卒中模型，一过性大脑中动脉闭塞 (TMCAO)给P21小鼠。 我们假设病毒感染引起的动脉病变加重了髓系细胞中的儿童中风- 依赖的态度。我们将在P18检查病毒感染在产生血管炎症中的作用， 动脉病变和改变白细胞表型(目标1)，确定是否抑制其中一个白细胞的募集 或中性粒细胞信号减弱感染后血管炎症和损伤的加重 儿童卒中(目标2)，并确定单核细胞VS的作用。中性粒细胞信号在增强受阻中的作用 儿童中风前感染后的脑连通性(目标3)。我们将利用几种药物 和体内的遗传策略，以干扰信号传递或取消髓系细胞的个别亚群的运输 使用新工具检查体内血管重新映射与大脑连通性和长时间... 期末功能结局。在感染和/或中风后从青少年大脑中分离的血管中，我们将 进一步检查血管炎症和内皮激活模式。记者Lys-EGFP-KI的使用 CCR2介导的单核细胞转运存在缺陷的小鼠和报道小鼠将能够可视化髓系 细胞，将它们与大脑免疫细胞区分开来，并识别白细胞的表型变化。纵向 多模式磁共振成像将无创性地描绘中风的严重程度、复发和出血性转化 病毒感染的增强，并描绘血管结构的变化(磁共振血管成像)。我们将研究 对男性和女性的影响，因为CAI在男孩中比女孩更常见，以及先天的保护作用 免疫受体可能与性别有关。我们独特的识别如何通过以下方式改善儿童中风的能力 感染引发的动脉病变后改变白细胞表型将严重促进 了解CAI并确定新的药理靶点。

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