CINC-1 as a modulator of blood-brain barrier integrity after neonatal stroke

越来越多的人认识到，出生时中枢神经系统的不成熟会影响缺血性损伤和恢复；因此，显然需要制定适合年龄的干预策略。成熟的血脑屏障（BBB）可以精确控制进入或离开大脑的物质。在包括中风在内的许多脑部疾病中，血脑屏障的破坏是造成损伤的一个重要因素。新出现的数据显示，血脑屏障是与生俱来的，在正常情况下可以有效地发挥功能，但尚不清楚它是如何受到生命早期脑损伤的影响的。我们在新生大鼠中的最新数据显示，短暂性脑缺血后血脑屏障对蛋白质的通透性得以保留，尽管存在细胞因子诱导的中性粒细胞化学活性蛋白1 （cinc1）的明显短暂积累，但中性粒细胞的转运被停止。这与成人大脑形成鲜明对比，在成人大脑中，血脑屏障的破坏发生得较早，并由趋化因子驱动的中性粒细胞浸润到缺血再灌注组织中介导。我们的目标是了解赋予耐药性的机制

It is increasingly recognized that the immaturity of the CNS at birth affects ischemic injury and recovery; thus there is an obvious need to develop age-appropriate strategies for intervention. The mature blood-brain barrier (BBB) allows precise control of substances that enter or leave the brain. In many brain diseases, including stroke, BBB breakdown is an important contributing factor to injury. Emerging data show that the BBB is developed by birth and functions effectively under normal conditions, bul il is unclear how it is affected by brain injury early in life. Our recent data in neonatal rats show that BBB permeability to proteins is preserved following transient cerebral ischemia, and neutrophil transmigration is halted despite the presence of marked transient accumulation of the cytokine-induced neutrophil chemoaUractant protein 1 (CINC-1). This is in stark contrast to the adult brain where disruption of the BBB occurs early and is mediated by chemokine·driven neutrophil infiltration into ischemic-reperfused tissue. Our goal is 10 understand the mechanisms that confer resistance of the BBB following early post-ischemia in neonates and contribu te to protection by studying the role of CINC·l in neutrophlilransmigralion and barrier integrity. We therefore propose to test the hypothesis that CINC-l protects neonatal brain by preserving blood-brain barrier integrity acutely after stroke. We will determine whether circulating CINC-1 protects BBB integrity (Aim 1) and limits neutrophil activation and migration (Aim 2) acutely after neonatal stroke. Studies will be accomplished in postnatal day 7 rats subjected to focal transient middle cerebral artery (MCA) occlusion and identified as injured by diffusion-weighted MRt during occlusion. We will use several experimental approaches, including flow cylometry, immunohistochemistry, cytokine multiplex, and MRi in animals with manipulated systemic CINC·l levels, or manipulated neutrophils.