PRENATAL ALCOHOL, INTEGRINS, AND NEURONAL MIGRATION DISORDER

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。产前酒精暴露会扰乱大脑的正常发育，导致严重的认知和行为障碍，包括儿童的多动症、学习障碍、注意力问题、自闭症和抑郁症。正常的大脑发育依赖于神经元沿着特定路径向其适当靶点的引导迁移。大多数未成熟神经元沿着放射状胶质纤维支架迁移。酒精诱导的次优神经元迁移被认为是中枢神经系统功能障碍导致神经行为问题的机制之一。在儿童中，怀孕期间暴露在酒精中的大脑包含异常分布在皮质深处的神经元簇。在动物模型中，出生前接触酒精也会改变神经元的迁移。异二聚体整合素受体，每个都包含一个α和一个β亚基，介导细胞与细胞和细胞外基质的相互作用，以及发育中的大脑中的细胞迁移。细胞黏附分子对神经元的迁移至关重要，现在已知与整合素亚基相互作用，并受整合素引发的细胞内信号控制。因此，干扰神经元和/或周围细胞的整合素功能将扰乱神经元的迁移。我们假设酒精暴露的胎儿神经元迁移不良是由于不同整合素受体和整合素转导的信号之间的协调改变所致。研究母亲饮酒对整合素亚单位表达的影响及其在分离的胎儿脑神经元迁移中的相对作用，可能有助于理解产前酒精介导的胎儿脑畸形的机制。在这项拟议的研究中，怀孕的大鼠将通过已知的干扰胎儿大脑中神经元迁移的方案暴露在酒精中。与层粘连蛋白相互作用的整合素亚单位的表达将在妊娠18天和20天期间在正常和酒精暴露的胚胎大鼠大脑半球中进行检测，届时大多数神经元将迁移。胎儿期酒精暴露对分离的胎儿大脑半球分离的神经元迁移率的影响将使用额外的细胞基质包裹的玻璃纤维分析来检测。已知参与神经元迁移的整合素亚单位的抗体将在玻璃纤维分析中应用，以评估每个整合素亚单位在对照组和酒精暴露胎儿大脑皮层神经元迁移中的相对贡献。这项研究的结果将确定整合素亚单位及其可能的异源二聚体，它们在妊娠18天和20天的大鼠大脑半球的皮质神经元迁移中最关键，并且是产前酒精的靶标。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Prenatal alcohol exposure can disrupt normal development of brain leading to profound cognitive and behavioral dysfunction including hyperactivity, learning disability, attention problems, autism and depression in children. Normal brain development depends on the guided migration of neurons along specific pathways to their appropriate targets. Most immature neurons migrate along a radial glial fiber scaffold. Suboptimal neuronal migration induced by alcohol has been implicated as a mechanism for central nervous system dysfunction leading to neurobehavioral problems. In children, brains exposed to alcohol during gestation contain clusters of neurons abnormally distributed throughout the depth of cortex. Prenatal exposure to alcohol also alters neuronal migration in animal models. Heterodimeric integrin receptors each containing an alpha and a beta subunit, mediate cell-cell and cell-extracellular matrix interactions, and cell migration in the developing brains. Cell adhesion molecules critical to neuronal migrations are now known to interact with integrin subunits and to be controlled by intracellular signals elicited by integrins. Therefore, interference with integrin function in neurons and/or surrounding cells would disrupt neuronal migration. We hypothesize that poor neuronal migration in alcohol-exposed fetuses is due to altered co-ordination amongst different integrin receptors and signals transduced by integrins. Studying effects of maternal alcohol consumption on the expression of integrin subunits and their relative contribution in the migration of neurons isolated from fetal brains may allow understanding the mechanisms of prenatal alcohol-mediated fetal brain malformations. In the proposed investigation, pregnant rats will be exposed to alcohol by regimens known to interfere with neuronal migration in fetal brains. Expression of integrin subunits that interact with laminin will be examined in normal and alcohol-exposed embryonic rat cerebral hemispheres during gestation days 18 and 20 when majority of neurons migrate. Effects of prenatal alcohol-exposure on the migration rates of dissociated neurons isolated from the fetal cerebral hemispheres will be examined using an extra cellular matrix-coated glass fiber assay. Antibodies against integrin subunits known to be involved in the neuronal migration will be applied during glass fiber assay to assess relative contribution of each integrin subunit in the migration of cerebral cortical neurons from control and alcohol-exposed fetuses. Results from this study will identify integrin subunits and their possible heterdimers that are most crucial in the migration of cortical neurons in gestation days 18 and 20 rat cerebral hemispheres and are targets of prenatal alcohol.