PRENATAL ALCOHOL, INTEGRINS, AND NEURONAL MIGRATION DISORDER

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，但不一定是研究者所在的机构。 产前酒精暴露会破坏大脑的正常发育，导致严重的认知和行为功能障碍，包括儿童多动症、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沿着特定的通路向其适当的靶点的引导迁移。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导致神经行为问题的中枢神经系统功能障碍的机制。 在儿童中，怀孕期间暴露于酒精的大脑含有异常分布在整个皮层深度的神经元簇。产前暴露于酒精也改变了动物模型中的神经元迁移。异二聚体整联蛋白受体各自含有α和β亚基，介导细胞-细胞和细胞-细胞外基质相互作用，以及发育中的脑中的细胞迁移。细胞粘附分子对神经元迁移至关重要，现在已知与整合素亚基相互作用，并由整合素引起的细胞内信号控制。因此，干扰神经元和/或周围细胞中的整合素功能将破坏神经元迁移。 我们推测，酒精暴露的胎儿神经元迁移差是由于不同的整合素受体和整合素转导的信号之间的协调改变。研究母亲饮酒对整合素亚基表达的影响及其在从胎儿脑中分离的神经元迁移中的相对贡献可能有助于了解产前酒精介导的胎儿脑畸形的机制。 在拟议的研究中，将通过已知干扰胎脑神经元迁移的方案使妊娠大鼠暴露于酒精。与层粘连蛋白相互作用的整合素亚基的表达将在妊娠第18天和第20天期间的正常和暴露于酒精的胚胎大鼠大脑半球中进行检查，此时大多数神经元迁移。将使用细胞外基质包被的玻璃纤维测定法检查产前酒精暴露对从胎儿大脑半球分离的游离神经元迁移率的影响。在玻璃纤维试验期间应用已知参与神经元迁移的整联蛋白亚基抗体，以评估各整联蛋白亚基在对照和酒精暴露胎仔大脑皮质神经元迁移中的相对贡献。从这项研究的结果将确定整合素亚基和他们可能的heterdimers是最关键的皮质神经元在妊娠第18和20天大鼠大脑半球的迁移，是产前酒精的目标。

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.