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: 2685700
• 负责人: Wesley David LUST
• 金额: $ 23.1万
• 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/2685700
• 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（改编自申请人摘要）： 最近的研究表明，神经元疾病密切相关， 产前事件和一个主要的危险因素似乎是胎儿 缺氧 努力减少新生儿疾病的发生率， 阻碍的事实是，很少有人知道或正常代谢， 发育中的胎儿大脑或与胎儿相关的病理生理学 痛苦 本应用程序将重点关注年龄相关的变化， 区域脑代谢，对营养供应减少的影响， 发育中的胎儿大脑;最后，关于 缺氧/缺血改变正常脑发育和/或引起缺氧 细胞损伤。 胎儿缺氧模型涉及子宫闭塞 妊娠大鼠卵巢动脉的子宫分支。 这些实验旨在回答一些问题， 对于进一步理解 胎儿脑窘迫和新生儿功能障碍：1）年龄依赖性变化 在正常发育的大脑中，新陈代谢会影响对伤害的反应吗？ 2)大脑的所有区域对代谢压力的反应都相似吗 独立的年龄，或者有窗口的易感性不同 区域？3)损伤持续时间和胎龄有多重要 胎儿的存活和大脑的正常发育？（4）有 可以最大限度地减少胎儿缺氧后损害的干预措施？ 具体目的是：1）表征围产期细胞损伤 脑缺氧损伤后，在不同的妊娠时间，使用 组织化学、免疫细胞化学和原位杂交技术; 2） 表征不同胎龄的正常代谢及其 对增加2支血管闭塞时间的反应，并将 代谢变化的区域模式的损害; 3），以确定能力 的大脑恢复代谢损伤后解除闭塞 血管，并检查神经递质和第二 信使;和4）评估潜在的神经保护作用， 在不同的妊娠期高血糖。 侮辱的严重性将 通过代谢物的定量组织化学测量进行评估， 纳克的大脑碎片，纳升的脑脊液和胎儿血液。 的 结果是各种胎儿脑区室的生化谱， E11至E21将反映胎儿发育期间的代谢变化， 与不同围产期观察到的损伤模式有关。 结果将产生一个动态的关键代谢和 发育过程中的结构事件，以及缺氧如何改变这些 关系，并将为制定新的战略提供基础， 尽量减少胎儿窘迫后新生儿脑功能障碍。