L1 function and sensitivity to ethanol

描述（由申请人提供）：人在子宫内暴露于高水平乙醇可导致各种神经异常，统称为“酒精相关神经发育障碍”（ARND）。观察到的ARND病例的一些特征与细胞粘附分子（CAM） L1突变个体的特征惊人地相似。这就产生了L1是乙醇靶点的假设，与这一观点一致的是，许多L1依赖的功能，包括神经元迁移、轴突延伸、轴突束化和髓鞘形成，特别容易受到乙醇暴露的影响。这项拨款的总体目标是确定乙醇作用于l1依赖性轴突延伸的性质和机制。具体而言，本研究旨在研究乙醇对L1的表面表达、轴突极化和膜流动性的影响，并确定乙醇降低L1依赖性轴突生长的机制。这项工作的数据将直接解决胎儿酒精暴露对正常神经连接发育的影响，也将与创伤性脑损伤或中风后的恢复机制相关，在这些机制中，许多发育调节分子重新表达，功能恢复受到乙醇的损害。

DESCRIPTION (provided by applicant): In utero exposure of humans to high levels of ethanol can result in a variety of neurological anomalies collectively termed "alcohol related neurodevelopmental disorders" (ARND). Some of the hallmarks of observed cases of ARND bear a striking similarity to those seen in individuals with mutations in the cell adhesion molecule (CAM) L1. This has given rise to the hypothesis that L1 is a target for ethanol, and consistent with this idea, many L1-dependent functions including neuron migration, axon extension, axon fasciculation and myelination are particularly vulnerable to ethanol exposure. The overall goals of this grant are to determine the nature and mechanism of ethanol actions on L1-dependent axon extension. Specifically, the proposal is to examine the effects of ethanol on the surface expression, axonal polarization and membrane fluidity of L1, and to identify the mechanism by which ethanol decreases L1-dependent axon outgrowth. The data from this work will directly address the effects of fetal alcohol exposure on the development of normal neural connectivity, and will also have relevance for mechanisms of recovery following traumatic brain injury or stroke, where many developmentally regulated molecules become re-expressed and recovery of function is impaired by ethanol.