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: 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
• 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

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