Mechanisms of Ischemic Neonatal Brain Injury

要求提供支持以继续一项多学科计划，该计划最初是作为P20项目开始的，以回应NINDS的RFA，然后是1997年的计划项目。该计划将继续以综合的方法探索基因表达、祖细胞和细胞死亡途径在预防新生儿脑缺血损伤中的作用。通过对围产期窒息、局灶性短暂性新生儿缺血和新生儿感染等多种病理状态的研究，将阐明缺血性新生儿细胞死亡的模式和机制。结合人类研究和基础科学研究，我们计划研究这些因素在新生儿缺血性脑损伤发病机制中的作用。根据我们在人类条件下观察到的情况，我们将继续探索基因表达和细胞死亡的新途径，以及使用现有的动物模型和组织培养范例，并利用既定的方法学来揭示机制并将其与神经行为结果联系起来。通过MRI/MRS对损伤的连续原位监测，我们可以更好地研究这些机制，并实现我们的最终目标--为缺血性脑损伤提供托儿所的治疗。每个项目在概念上是相互关联的，并利用集中设施的科学核心进行实验操作。该计划的四个项目是：1)磁共振参数作为新生儿急性缺氧缺血性损伤预后的预测因子，2)缺氧诱导基因在新生儿脑损伤中的作用，3)caspase依赖和独立损伤的作用，4)齿状回损伤在新生儿脑膜炎中的作用。行政核心A将负责统计支持和数据管理，组织年度进度会议和每月数据小组。核磁共振核心B和神经行为核心C都将通过管理核心整合从四个项目获得的信息。通过这些不同的努力，我们将研究未成熟神经系统缺血的细胞、分子和生理机制，以开发新的治疗方法。

Support is requested to continue a multidisciplinary program that was begun initially as a P20 in response to an RFA from NINDS, and then as a Program Project in 1997. This program will continue to explore in an integrated approach the role of gene expression, progenitor cells, and cell death pathways in the prevention of ischemic injury to the neonatal brain. Through the study of a variety of pathological states such as perinatal asphyxia, focal transient neonatal ischemia and neonatal infection, patterns and mechanisms of ischemic neonatal cell death will be elucidated. With both human research and basic science research, we plan to study the role of these factors in the pathogenesis of neonatal ischemic brain injury. Taking what we observe in the human condition, we will continue to explore novel pathways of gene expression and cell death, as well as use existing animal models and tissue culture paradigms with established methodology to unravel mechanisms and relate them to neurobehavioral outcomes. Through continuous in situ monitoring of injury via MRI/MRS, we are better equipped to study these mechanisms and meet our ultimate goal of providing therapies in the nursery for ischemic brain injury. Each project is conceptually interrelated and utilizes the scientific cores for centralized facilities for experimental manipulations. The four projects of the program are: 1) Magnetic resonance parameters as predictors of outcome in acute neonatal hypoxic-ischemic injury, 2) Role of hypoxia inducible genes in neonatal brain injury, 3) Role of caspase dependent and independent injury and 4) Dentate gyrus injury in neonatal meningitis. The administrative core A will house the statistical support and data management, organize the yearly progress meeting and monthly data panels. Both the MRI Core B and the Neurobehavioral Core C will integrate information gained from the four projects through the administrative core. Through these varied efforts, we will investigate the cellular, molecular and physiological mechanisms of ischemia in the immature nervous system with the goal of developing novel therapies.