CONSEQUENCES OF FETAL HYPOXIA ON THE NEONATAL CNS

胎儿缺氧对新生儿中枢神经系统的影响

• 批准号: 2037773
• 负责人: Wesley David LUST
• 金额: $ 23.75万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2037773
• 关键词: bioenergetics; blood glucose; brain metabolism; central nervous system; congenital brain disorder; developmental neurobiology; embryo /fetus hypoxia; gestational age; glucose metabolism; histology; hyperglycemia; immunocytochemistry; in situ hybridization; laboratory rat; lactic acidosis; neuroanatomy; neuroprotectants; neurotransmitters; second messengers

DESCRIPTION (Adapted from applicant's abstract) : Recent studies have shown that neuronal disorders closely correlate with prenatal events and one of the major risk factors appears to be fetal hypoxia. Efforts to minimize the incidence of neonatal disorders have been hindered by the fact that little is known about either normal metabolism in the developing fetal brain or the pathophysiology associated with fetal distress. This application will focus on the age-dependent changes in regional brain metabolism, on the effect of reduced supply of nutrients to the developing fetal brain; and, finally, on the time threshold for hypoxia/ischemia to alter normal brain development and/or elicit hypoxic cell damage. The fetal hypoxia model involves occlusion of the uterine artery and the uterine branch of the ovarian artery in pregnant rats. These experiments are designed to answer a number of questions that are fundamental to furthering the understanding of the relationship between fetal brain distress and neonatal dysfunction: 1) Do age-dependent changes in normal developing brain metabolism influence the response to an insult?; 2) Do all regions of the brain respond similarly to a metabolic stress independent of age, or are there windows of susceptibility for different regions?; 3) How critical are the duration of the insult and gestational age to fetal survival and normal development of the brain?; and 4) Are there interventions which can minimize damage following fetal hypoxia? The specific aims are: 1) To characterize cell damage in the perinatal brain following hypoxic insults at various gestational times using histochemical, immunocytochemical and in situ hybridization techniques; 2) To characterize normal metabolism at various gestational ages and its responses to increasing periods of 2-vessel occlusion, and to relate the metabolic changes to regional pattern of damage; 3) To determine the ability of the brain to recover metabolically from the insult upon de-occlusion of the vessels and examine posthypoxic changes in neurotransmitters and second messengers; and 4) To evaluate the potential neuroprotective effect of hyperglycemia at various gestational times. The severity of the insult will be assessed by quantitative histochemical measurement of metabolites in nanogram pieces of brain, nanoliters of CSF and in fetal blood. The resulting biochemical profile of the various fetal brain compartments from E11 to E21 will reflect metabolic changes during fetal development, and will be related to the patterns of damage observed at varying perinatal times. The results will yield a dynamic picture of the critical metabolic and structural events during development, and how hypoxia may alter these relationships, and will provide a basis for developing novel strategies to minimize neonatal brain dysfunction following fetal distress.

描述(改编自申请人的摘要)： 最近的研究表明，神经元障碍与 产前事件和主要危险因素之一似乎是胎儿 缺氧。努力将新生儿疾病的发生率降至最低 受阻于对两种疾病的正常新陈代谢知之甚少的事实 发育中的胎儿大脑或与胎儿相关的病理生理学 苦恼。此应用程序将重点关注 局部大脑代谢，对营养物质供应减少的影响 发育中的胎儿大脑；最后，在 缺氧/缺血改变正常脑发育和/或引起缺氧 细胞受损。胎儿缺氧模型涉及子宫闭塞 妊娠大鼠的卵巢动脉和子宫动脉分支。 这些实验旨在回答以下几个问题 对加深对两国关系的理解 胎脑窘迫和新生儿功能障碍：1)是否存在年龄相关性变化 在正常发育中，大脑新陈代谢会影响对侮辱的反应吗？ 2)大脑的所有区域对新陈代谢压力的反应都相似吗 与年龄无关，或者是否存在不同的易感窗口 地区？；3)侮辱的持续时间和孕周有多严重 对胎儿存活和大脑的正常发育有什么影响？ 哪些干预措施可以将胎儿缺氧后的损害降至最低？ 具体目标是：1)描述围产期细胞损伤的特征 在不同孕期低氧侮辱后的大脑 组织化学、免疫细胞化学和原位杂交技术；2) 不同胎龄的正常代谢特征及其临床意义 对2支血管闭塞时间增加的反应，并与 代谢改变对局部损害模式的影响；3)判断能力 在解除大脑阻塞后，从侮辱中新陈代谢地恢复 血管和检查缺氧后神经递质的变化和第二 以及4)评估其潜在的神经保护作用 不同孕期的高血糖。侮辱的严重性将会 通过代谢产物的定量组织化学测量来评估 纳克的脑片，纳升的脑脊液和胎儿血液。这个 由此得出的不同胎儿脑室的生化图谱 E11至E21将反映胎儿发育过程中的代谢变化，并将 与在不同围产期观察到的损伤模式有关。 结果将产生一幅关键的新陈代谢和 发育过程中的结构性事件，以及缺氧可能如何改变这些 关系，并将为制定新的战略提供基础 最大限度地减少胎儿窘迫后新生儿脑功能障碍。