Blood-brain barrier function after neonatal and pediatric experimental stroke

新生儿和儿童实验性卒中后的血脑屏障功能

• 批准号: 8469106
• 负责人: Zinaida S Vexler
• 金额: $ 15.52万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469106
• 关键词: Accounting; Acute; Acute Brain Injuries; Adolescent; Adult; Affect; Age; Animal Model; Animals; Beds; Behavior; Behavioral; Blood - brain barrier anatomy; Brain; Child; Childhood; Childhood stroke; Data; Diffusion Magnetic Resonance Imaging; Disease; Embryo; Endothelial Cells; Gene Expression Profile; Human; Image; Infiltration; Inflammation; Inflammatory; Injection of therapeutic agent; Injury; Ischemic Stroke; Knock-in Mouse; Leukocytes; Life; Microglia; Middle Cerebral Artery Occlusion; Modeling; Mus; Neonatal; Newborn Infant; Only Child; Outcome; Pattern; Peripheral; Permeability; Photons; Predisposition; Proteins; Rattus; Regulation; Relative (related person); Research; Rodent; Rodent Model; Stroke; Tight Junctions; Tissue-Specific Gene Expression; Toddler; Tracer; Translations; age group; age related; cytokine; human data; improved; injured; macrophage; monocyte; neonate; novel; postnatal; protein expression; rat endothelial barrier antigen; response; transcytosis

DESCRIPTION (provided by applicant): Pediatric stroke is an emerging field. Research in humans suggests that pediatric stroke differs from neonatal stroke, but there are no animal models that can help identify the mechanisms of pediatric stroke. Immaturity markedly affects the neuroinflammatory mechanisms of injury, as we showed in a rodent model of neonatal focal stroke and in a similar model in the adult. Furthermore, blood-brain barrier (BBB) integrity is strikingly better preserved in acute neonatal stroke than in adult stroke. While paradoxical, this conclusion is supported by several lines of evidence, including the functional and structural integrity of the BBB and the differential gene and protein expression of an array of BBB proteins. A study showing the disrupted BBB in juvenile rats but not in newborn rats following an intracerebral inflammatory challenge suggested that the susceptibility of the BBB to injury is age- dependent; thus, the response of the BBB to neonatal and pediatric stroke may differ greatly. We hypothesize that the mechanisms of pediatric and neonatal stroke differ in part due to the distinct maturational status of the BBB. To identify the differential BBB response of neonatal and juvenile brain to stroke, we wil focus on developmentaly regulated BBB mechanisms that are "mute" in neonatal rodents but active in juvenile rodents. We wil use our wel-characterized focal stroke models in postnatal day 7 (P7) rats and P9 mice and focal stroke models in juvenile rats and mice to determine if BBB integrity is disturbed after acute pediatric arterial stroke (Aim 1), and if microglia/monocytes differentially affect BBB permeability after neonatal and pediatric stroke (Aim 2). The functional and structural integrity of the BBB will be determined in animals with and without the additional challenge of tight junction integrity after stroke. The relationship between microglial activation and BBB permeability (intravascular tracers) wil be determined by 2-photon imaging of living Cx3cr1GFP/+ neonatal and juvenile mice after stroke. The extent of the involvement of peripheral and brain macrophages in injury and in the disruption of the BBB will be determined in novel Cx3cr1GFP/+/CCR2RFP/+ knock-in mice in both age groups.

描述（由申请人提供）：小儿冲程是一个新兴领域。人类的研究表明，小儿中风与新生儿中风不同，但没有动物模型可以帮助识别小儿中风的机制。正如我们在新生儿局灶性中风的啮齿动物模型和成人类似模型中所示的那样，不成熟会显着影响损伤的神经炎症机制。此外，与成人中风相比，血脑屏障（BBB）的完整性在急性新生儿中风中得到了明显保留的。虽然矛盾的是，该结论得到了多种证据的支持，包括BBB的功能和结构完整性以及一系列BBB蛋白的差异基因和蛋白质表达。一项研究表明，少年大鼠的BBB破坏了，但在脑内炎症性挑战之后没有新生大鼠的BBB，这表明BBB对受伤的敏感性取决于年龄。因此，BBB对新生儿和小儿中风的反应可能有很大差异。我们假设小儿和新生儿中风的机制部分由于BBB的独特成熟状态而有所不同。为了确定新生儿和青少年脑对中风的差异BBB反应，我们将专注于发育量调节的BBB机制，这些机制在新生儿啮齿动物中“静音”，但在少年啮齿动物中活跃。 We wil use our wel-characterized focal stroke models in postnatal day 7 (P7) rats and P9 mice and focal stroke models in juvenile rats and mice to determine if BBB integrity is disturbed after acute pediatric arterial stroke (Aim 1), and if microglia/monocytes differentially affect BBB permeability after neonatal and pediatric stroke (Aim 2). BBB的功能和结构完整性将在中风后有和没有紧密连接完整性的其他挑战的动物中确定。中风后生存的CX3CR1GFP/+新生儿和少年小鼠的2光片成像确定小胶质细胞激活与BBB渗透率（血管内示踪剂）之间的关系。在两个年龄段的新型CX3CR1GFP/+/CCR2RFP/+敲击小鼠中，将确定周围和脑巨噬细胞在损伤中的参与程度以及BBB的破坏程度。