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Polyamines in neonatal alcohol neurotoxicity

新生儿酒精神经毒性中的多胺

基本信息

批准号：
6929947
负责人：
SUSAN BARRON
金额：
$ 14.73万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2007-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): While it is well known that prenatal ethanol (ETOH) exposure has detrimental effects on the developing CNS, there are still numerous questions regarding the mechanisms underlying the CNS damage observed. The effects of ETOH on the glutamate/NMDA receptor (NMDAR) are well established. ETOH-induced alterations in NMDAR function during development causes hippocampal damage by at least two mechanisms; reduced NMDAR function during the presence of ETOH (via apoptosis) and enhanced NMDAR function during ETOH withdrawal (via excitotoxicity). Which of these mechanisms predominates may be age- dependent with suppression of NMDAR activity being more damaging at earlier developmental stages and overexcitation during ETOH WD being a more dominant component in older cultures. Polyamines are ubiquitous compounds that also play an important trophic role during CNS development and one of the mechanisms by which polyamines work is by potentiation of the NMDAR. Since hippocampal NMDAR subtypes and their response to polyamines change during the first neonatal weeks in rats, the timing when ETOH exposure occurs may have significant influences on response to polyamines, NMDAR and outcome. These hypotheses can be tested directly in vitro using the organotypic cell culture model and comparing cultures obtained from neonatal rats at PND 2 versus PND 8. The specific aims are 1) to examine how developmental age affects the response to ETOH as measured by cell damage in our in vitro organotyplc hippocampal model; 2) to examine how developmental age and ETOH exposure interact with polyamines as measured by cell damage in the in vitro hippocampal model and 3) To assess whether in vivo ETOH exposure correlates with the findings from in vitro exposure. The model proposed in this application will provide an innovative and novel approach for using hippocampal organotypic cell cultures to address specific developmental questions related to ETOH's effects and to assess the predictive validity of the model to predict in vivo results. With these findings, it may also be possible to gain a better understanding of some of the mechanisms underlying neonatal ETOH exposure and the role of polyamines that will provide grounds for pharmacological interventions that will reduce some of ETOH effects.

描述（由申请人提供）：虽然众所周知，产前乙醇（ETOH）暴露对胎儿有不利影响，发展中的中枢神经系统，仍然有许多问题的机制，观察到CNS损伤。ETOH对谷氨酸/NMDA受体（NMDAR）的作用是很好地建立了。发育过程中ETOH诱导的NMDAR功能改变至少两种机制导致海马损伤;存在期间NMDAR功能降低 ETOH（通过细胞凋亡）和ETOH戒断期间NMDAR功能增强（通过兴奋性毒性）。这些机制中哪一种占主导地位可能与年龄有关，抑制NMDAR活性在早期发育阶段更具破坏性，在ETOH WD期间的过度激发是较老文化中更占主导地位的成分。多胺是一种普遍存在的化合物，在中枢神经系统中也起着重要的营养作用。发展和多胺的工作机制之一是通过增强的 NMDAR。由于海马NMDAR亚型及其对多胺反应的变化，在新生大鼠的第一周，ETOH暴露发生的时间可能具有显著的对多胺、NMDAR反应和结局的影响。这些假设可以通过直接在体外使用器官型细胞培养模型，并比较从 PND 2与PND 8时的新生大鼠。具体目标是：（1）研究如何发展年龄影响ETOH的反应，通过我们的体外器官类型中的细胞损伤来测量。海马模型; 2）研究发育年龄和ETOH暴露如何与通过体外海马模型中的细胞损伤测量的多胺，以及3）评估体内ETOH暴露是否与体外暴露结果相关。模型本申请中提出的方法将提供一种创新的和新颖的方法，器官型细胞培养，以解决与ETOH效应相关的特定发育问题并评估模型预测体内结果的预测有效性。有了这些发现，也可能更好地了解一些潜在的机制，新生儿ETOH暴露和多胺的作用，这将为减少某些ETOH影响的药理干预提供依据。