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: 8358551
• 负责人: Zinaida S Vexler
• 金额: $ 29.02万
• 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/8358551
• 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. PUBLIC HEALTH RELEVANCE: Pediatric ischemic stroke occurs 1 in 3,000-5,000. Arterial ischemic stroke accounts for approximately 50% of strokes in children, and only 24% of children are neurologically normal after a stroke. It is important to understand the mechanisms of the disease to develop appropriate therapies and improve bench-to-bed translation in pediatric stroke.

描述（由申请人提供）：小儿中风是一个新兴领域。人类研究表明，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的类似模型中所显示的那样，不成熟显着影响损伤的神经炎症机制。此外，急性新生儿中风中的血脑屏障（BBB）完整性比成人中风中保存得更好。虽然矛盾，但这一结论得到了多项证据的支持，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表达。一项研究显示，在脑内炎症攻击后，幼年大鼠的血脑屏障受到破坏，但新生大鼠的血脑屏障并未受到破坏，这表明血脑屏障对损伤的敏感性与年龄有关。因此，血脑屏障对新生儿和儿童中风的反应可能有很大不同。我们假设儿童和新生儿中风的机制有所不同，部分原因是血脑屏障的成熟状态不同。为了确定新生儿和幼年大脑对中风的不同 BBB 反应，我们将重点关注发育调节的 BBB 机制，这些机制在新生啮齿动物中“静音”，但在幼年啮齿动物中活跃。我们将使用我们在出生后第 7 天 (P7) 大鼠和 P9 小鼠中充分表征的局灶性中风模型以及幼年大鼠和小鼠中的局灶性中风模型来确定急性儿科动脉中风后 BBB 完整性是否受到干扰（目标 1），以及小胶质细胞/单核细胞是否对新生儿和儿童中风后 BBB 通透性产生不同影响（目标 2）。 BBB 的功能和结构完整性将在中风后有或没有面临紧密连接完整性额外挑战的动物中确定。小胶质细胞激活和 BBB 通透性（血管内示踪剂）之间的关系将通过中风后活体 Cx3cr1GFP/+ 新生小鼠和幼年小鼠的 2 光子成像来确定。外周和脑巨噬细胞参与损伤和 BBB 破坏的程度将在两个年龄组的新型 Cx3cr1GFP/+/CCR2RFP/+ 敲入小鼠中确定。 公众健康相关性：小儿缺血性中风的发生率为 3,000-5,000 分之一。动脉缺血性中风约占儿童中风的50%，只有24%的儿童中风后神经功能正常。了解该疾病的机制对于开发适当的治疗方法并改善小儿卒中的临床转化非常重要。