PERINATAL HYPOXIC ISCHEMIC BRAIN DAMAGE

本计划项目提案的总体目标是提高我们对导致人类胎儿和新生儿缺氧缺血性脑损伤的病理生理机制的了解，并开发有效的策略来预防或最大限度地减少最终导致智力低下或发育障碍的永久性脑损伤。我们的具体目标包括：1)阐明围产期动物缺氧缺血性脑损伤发生的潜在细胞和分子机制；2)通过预适应、代谢和药物操作来探讨缺氧缺血性神经保护的机制；3)确定氧化应激和炎症介质在围产期缺氧缺血性脑损伤中的作用；4)研究围产期缺氧缺血性脑损伤对脑发育的影响；以及5)探讨癫痫持续状态在围产期缺氧缺血性脑损伤中的作用。计划项目建议包括7个基础研究项目和3个核心项目，后者包括行政和生物统计学核心、神经病理学核心以及磁共振波谱和成像核心。个人研究项目的标题是：1)氧化新陈代谢；2)能量新陈代谢；3)神经保护机制；4)炎症介质；5)氧化应激/GLIA；6)细胞分化；7)癫痫状态。该项目代表的科学学科包括儿科神经学、围产期学、神经科学、神经病理学、神经放射学、计算机科学和生物统计学。预计从所述研究工作中得出的结果将与必要的预防和治疗干预措施直接相关，以大大降低智力低下和发育障碍在人类婴儿和儿童发育中的重要性和严重程度。

The overall objective of the present Program Project proposal is to improve our understanding of the pathophysiologic mechanisms leading to hypoxic-ischemic brain damage in the human fetus and newborn infant and to develop effective strategies to prevent or minimize permanent brain damage which ultimately leads to mental retardation or developmental disability. Our specific aims include: 1) to elucidate underlying cellular and molecular mechanisms responsible for the occurrence of hypoxic-ischemic brain damage in perinatal animals; 2) to investigate mechanisms of hypoxic-ischemic neuroprotection through preconditioning and metabolic and pharmacologic manipulations; 3) to ascertain the contribution of oxidative stress and inflammatory mediators to the production of perinatal hypoxic-ischemic brain damage; 4) to study the effects of perinatal hypoxic-ischemic brain damage on short- and long-term cerebral development; and 5) to investigate the role of status epilepticus in perinatal hypoxic-ischemic brain damage. Included in the Program Project Proposals are 7 basic research projects and 3 Core projects, the latter to include an Administrative and Biostatistics Core, Neuropathology Core, and MR spectroscopy and imaging Core. The individual research project titles are: 1) Oxidative Metabolism; 2) Energy Metabolism; 3) Neuroprotective Mechanisms; 4) Inflammatory Mediators; 5) Oxidative Stress/Glia; 6 Cellular Differentiation; and 7) Status Epilepticus. Scientific disciplines represented in the Program Project include pediatric neurology, perinatology, neuroscience, neuropathology, neuroradiology, computer science and biostatistics. It is anticipated that the findings derived from the described research endeavors will have direct relevance to preventative and therapeutic interventions necessary to reduce substantially the significance and severity of mental retardation and developmental disability in developing human infants and children.