The Role of Lipid Rafts in Fetal Alcohol Spectrum Disorder

脂筏在胎儿酒精谱系障碍中的作用

基本信息

批准号：
7881454
负责人：
CYNTHIA FRANCES BEARER
金额：
$ 29.7万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7881454
关键词：
Acids Alcohol-related birth defects Alcohols Animals Behavioral Brain Cell membrane Cells Cholesterol Choline Cysteine Cytoplasmic Granules Data Defect Development Developmental Neurotoxicity of Ethanol Dietary Intervention Endocytosis Ethanol Ethanol toxicity Fetal Alcohol Spectrum Disorder Fetal Alcohol Syndrome Figs - dietary Folic Acid Ganglioside GM1 Growth Cones Heavy Drinking Homing Human In Vitro Incidence Infant Intervention Kinetics Live Birth Measures Mediating Membrane Microdomains Mental Retardation Modeling Mus NAPVSIPQ peptide Nervous system structure Neural Cell Adhesion Molecule L1 Neural Tube Defects Neuraxis Neurites Neurons Newborn Infant Nutrient Outcome Pathway interactions Peripheral Pregnancy Protective Agents Proteins Psychological Tests Public Health Rattus Recycling Research Research Personnel Role Secondary to Signal Transduction Site Supplementation System Teratogens Test Result Testing Toxic effect Trefoil Motif Work alcohol effect alcohol exposure alcohol sensitivity base cost drinking in vivo in vivo Model mutant nervous system development neurofascin neurotoxicity prevent programs protein distribution protein protein interaction pup trafficking

项目摘要

DESCRIPTION (provided by applicant): Ethanol is a known human teratogen of immense public health impact. Heavy drinking during pregnancy is the leading known cause of mental retardation, while more subtle effects particularly on the developing brain occur in 1% of all liveborns. Recent evidence has shown that many of the known protein targets for ethanol's toxic effects on the developing central nervous system are associated with lipid rafts. Lipid rafts are specialized microdomains of the plasma membrane and serve as platforms for protein-protein interactions. Our prior work has shown that the ability of L1 cell adhesion molecule (L1), a protein critical for the proper development of the nervous system, to promote neurite outgrowth is exquisitely sensitive to ethanol. Localized disruption of lipid rafts reduces L1 mediated neurite outgrowth. Our preliminary data show that ethanol alters the distribution of L1 in lipid rafts, and that cholesterol depletion abolishes ethanol sensitivity. Further, our preliminary data suggests that other protein targets of ethanol change their lipid raft distribution in the presence of ethanol. We hypothesize that a major mechanism of ethanol toxicity is through alteration of lipid raft-protein interactions, and that interventions which reduce toxicity prevent this disruption. These hypotheses will be tested using cerebellar granule neurons (CGN) from rat pups and from mice, both wild type and lacking L1, and a rat in vivo entubation model. In Aim 1, we will confirm that lipid raft-L1 interactions underlie ethanol sensitivity of neurite outgrowth by transfecting CGN lacking L1 with mutant constructs of L1 lacking a signal to colocalize with lipid rafts. Neurite outgrowth in transfected cells is expected to be ethanol insensitive. In Aim 2, we will determine whether L1 or the lipid raft is the site of the ethanol action, and the effect of ethanol on the kinetics of L1 trafficking to and out of the lipid raft compartment. In Aim 3, we will use four nutrients shown to be protective in other experimental systems, to prevent the changes in protein distribution secondary to ethanol. The most effective combination of these nutrients will be determined with L1 in CGN and in the in vivo model. The relevance of this research is that simple dietary manipulations with these nutrients may prevent some aspects of ethanol neurotoxicity much like folic acid supplementation and reduction of neural tube defects.

描述（由申请人提供）：乙醇是对公共卫生影响巨大影响的知名人类伤害。怀孕期间的大量饮酒是智力低下的主要原因，而尤其是对发育中的大脑的更微妙的影响发生在所有活生生中的1％中。最近的证据表明，许多已知的乙醇对发展中枢神经系统毒性作用的蛋白质靶标与脂质筏有关。脂质筏是质膜的专门微域，并用作蛋白质 - 蛋白质相互作用的平台。我们先前的工作表明，L1细胞粘附分子（L1）的能力（L1）是神经系统适当发育至关重要的蛋白质，促进神经突生长对乙醇非常敏感。脂质筏的局部破坏可减少L1介导的神经突生长。我们的初步数据表明，乙醇会改变L1在脂质筏中的分布，并且胆固醇的耗竭消除了乙醇敏感性。此外，我们的初步数据表明，乙醇的其他蛋白质靶标在存在乙醇的情况下会改变其脂质筏的分布。我们假设乙醇毒性的主要机制是通过改变脂质筏蛋白相互作用，而降低毒性的干预措施则阻止了这种破坏。这些假设将使用大鼠幼崽的小脑颗粒神经元（CGN）进行测试，以及来自野生型和缺乏L1的小鼠以及体内摄入模型的大鼠。在AIM 1中，我们将确认通过转染CGN缺乏L1的L1突变构建体的L1缺乏信号无法与脂质筏共定位的CGN通过转染CGN，这是神经突生长的乙醇敏感性的基础。转染细胞中的神经突生长有望是乙醇不敏感的。在AIM 2中，我们将确定L1或脂质筏是乙醇作用的部位，以及乙醇对L1运输动力学对脂质筏室的影响。在AIM 3中，我们将使用在其他实验系统中显示的四种营养物质，以防止继发于乙醇的蛋白质分布的变化。这些营养素的最有效组合将在CGN和体内模型中用L1确定。这项研究的相关性是，这些营养素的简单饮食操纵可能会阻止乙醇神经毒性的某些方面，例如补充叶酸和减少神经管缺陷。