Mechanisms of ethanol-induced neurodevelopmental effects

乙醇诱导神经发育效应的机制

基本信息

批准号：
8147829
负责人：
Marina Guizzetti
金额：
$ 30.25万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-25 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8147829
关键词：
Address Affect Alcohols Alzheimer&apos s Disease Apolipoprotein E Apolipoproteins Astrocytes Atherosclerosis Binding Brain Brain Injuries Calories Cell Proliferation Cells Cholesterol Cholesterol Homeostasis Coculture Techniques Conditioned Culture Media Congenital Abnormality Country Cultured Cells Development Developmental Neurotoxicity of Ethanol Diet Employee Strikes Ethanol Event Exposure to Fetal Alcohol Exposure Fetal Alcohol Syndrome Fetal Development Fetus Foundations Gel Chromatography Generations Genetic Transcription Guidelines Health Homeostasis Immunohistochemistry In Vitro Inborn Genetic Diseases Incubated Injury Investigation Lead Lipids Lipoproteins Liquid substance Malnutrition Mediating Membrane Membrane Microdomains Mental Retardation Microcephaly Mutation NIH Program Announcements Neocortex Neuraxis Neurites Neurons Phospholipase D Phospholipids Play Population Pregnancy Pregnant Women Prevalence Production Proteins Rattus Research Personnel Risk Role Signal Transduction Pathway Small Interfering RNA Smith-Lemli-Opitz Syndrome Sonic Hedgehog Pathway South Africa System Testing Tissues Up-Regulation alcohol effect cholesterol biosynthesis cholesterol trafficking cholesterol transporters experience feeding in vivo in vivo Model lipoprotein cholesterol neuron development neuronal survival neurotrophic factor novel pregnant research study response synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): This proposal will address a novel aspect of ethanol's developmental neurotoxicity, i.e. its effect on cholesterol homeostasis in the central nervous system. While too much cholesterol may be deleterious, as in case of atherosclerosis and Alzheimer's disease, too little can produce birth defects. Different degrees of mental retardation are often observed in inborn errors of cholesterol synthesis such as Smith-Lemli-Opitz syndrome. Lack of cholesterol during brain development as a consequence of these genetic defects leads to severe brain damage, including microcephaly and mental retardation, both of which are hallmarks of the fetal alcohol syndrome. The effects of ethanol on cholesterol homeostasis in the developing brain have not been investigated. In the brain, cholesterol is mostly produced endogenously, and its homeostasis is regulated by endogenously produced lipoproteins and cholesterol transporters. This proposal will investigate the hypothesis that ethanol, by upregulating cholesterol transporters and lipoprotein production by central nervous system cells, will increase the clearance of cholesterol from the brain, causing cholesterol depletion. Low levels of cholesterol are consistent with some of the effects caused by in utero alcohol exposure such as inhibition of the sonic hedgehog pathway, neuronal development and survival, and cell proliferation. Specific Aims of the proposal are: 1) The investigation of the role of ABCA1 and ABCG1 in ethanol-induced cholesterol efflux. The effect of ethanol on cholesterol efflux and cholesterol levels will be investigated in cortical neurons in vitro; in addition, the role of ABCA1, ABCG1, and phospholipase D in ethanol-induced upregulation of cholesterol efflux and cholesterol transporter induction in astrocytes and, possibly, in neurons will be examined by selectively removing these proteins form astrocyte and neuron cultures. 2) The investigation of the effect of ethanol on astrocyte-generated lipoproteins and their interaction with neurons. The effect of ethanol on the composition of astrocyte-produced lipoproteins separated by gel filtration, and their role on cholesterol efflux from neurons will be analyzed. Furthermore, the effect of ethanol on lipoprotein composition and cholesterol efflux will be examined in an astrocyte/neuron co- culture system. 3) The investigation of the effect of in vivo ethanol administration on ABC cholesterol transporters and on cholesterol levels in the developing brain. The effect of in vivo exposure to ethanol during gestation on the cholesterol transporters ABCA1 and ABCG1 transcription and expression in neurons and astrocytes and on cholesterol levels will be assessed in the neocortex of rat fetuses at gestational day 21. Altogether, these studies are directed at characterizing a possible novel mechanism involved in ethanol-induced neurodevelopmental effects, i.e. its effects on cholesterol homeostasis in the brain. PUBLIC HEALTH RELEVANCE The proposed studies on the effect of ethanol on cholesterol homeostasis in the developing brain were prompted by the observation that several of the neurodevelopmental effects caused by ethanol are consistent with effects caused by lack of cholesterol. Cholesterol is indeed necessary for various aspects of brain development. We hypothesized that ethanol, by mechanisms to be investigated in the proposed project, may affect cholesterol homoeostasis and reduce cholesterol levels in the developing brain. The most recent discoveries in the field of cholesterol trafficking will be applied to the investigation of the effects of ethanol on cholesterol transporters, lipoprotein generation and, ultimately, cholesterol levels in the developing brain. As cholesterol is a regular component of the diet, our studies could potentially lead to the revision of dietary guidelines for pregnant women at risk. It may also help understanding why in some very poor regions of South Africa the prevalence of FAS is much higher than in Western countries as these populations also experience severe malnutrition.

描述（由申请人提供）：该提案将解决乙醇发育神经毒性的一个新方面，即它对中枢神经系统胆固醇稳态的影响。虽然过多的胆固醇可能有害，如动脉粥样硬化和阿尔茨海默病，但胆固醇过少会导致出生缺陷。胆固醇合成先天性缺陷，如 Smith-Lemli-Opitz 综合征，经常观察到不同程度的智力低下。由于这些遗传缺陷，大脑发育过程中胆固醇缺乏会导致严重的脑损伤，包括小头畸形和智力低下，这两者都是胎儿酒精综合症的标志。乙醇对发育中大脑胆固醇稳态的影响尚未得到研究。在大脑中，胆固醇主要是内源性产生的，其稳态由内源性产生的脂蛋白和胆固醇转运蛋白调节。该提案将研究以下假设：乙醇通过上调中枢神经系统细胞的胆固醇转运蛋白和脂蛋白产生，将增加大脑中胆固醇的清除，从而导致胆固醇消耗。低水平的胆固醇与子宫内酒精暴露引起的一些影响是一致的，例如抑制声波刺猬通路、神经元发育和存活以及细胞增殖。该提案的具体目标是： 1) 研究 ABCA1 和 ABCG1 在乙醇诱导的胆固醇流出中的作用。将在体外研究皮质神经元中乙醇对胆固醇流出和胆固醇水平的影响；此外，通过从星形胶质细胞和神经元培养物中选择性去除这些蛋白质，将检查ABCA1、ABCG1和磷脂酶D在星形胶质细胞和可能的神经元中乙醇诱导的胆固醇流出上调和胆固醇转运蛋白诱导中的作用。 2）乙醇对星形胶质细胞生成脂蛋白的影响及其与神经元相互作用的研究。将分析乙醇对通过凝胶过滤分离的星形胶质细胞产生的脂蛋白的组成的影响，以及它们对神经元胆固醇流出的作用。此外，将在星形胶质细胞/神经元共培养系统中检查乙醇对脂蛋白组成和胆固醇流出的影响。 3) 研究体内乙醇对 ABC 胆固醇转运蛋白和发育中大脑中胆固醇水平的影响。妊娠期间体内暴露于乙醇对神经元和星形胶质细胞中胆固醇转运蛋白 ABCA1 和 ABCG1 转录和表达以及胆固醇水平的影响将在妊娠第 21 天的大鼠胎儿新皮质中进行评估。总而言之，这些研究旨在表征一种可能涉及乙醇诱导的神经发育效应的新机制，即它对大脑中胆固醇稳态的影响。公共健康相关性乙醇对发育中大脑胆固醇稳态影响的拟议研究是由于观察到乙醇引起的一些神经发育影响与缺乏胆固醇引起的影响一致而提出的。胆固醇确实对于大脑发育的各个方面都是必需的。我们假设，通过拟议项目中待研究的机制，乙醇可能会影响胆固醇稳态并降低发育中大脑中的胆固醇水平。胆固醇运输领域的最新发现将应用于研究乙醇对胆固醇转运蛋白、脂蛋白生成以及最终对发育中大脑中胆固醇水平的影响。由于胆固醇是饮食中的常规成分，我们的研究可能会导致修订针对高危孕妇的饮食指南。它还可能有助于理解为什么在南非一些非常贫困的地区，FAS 的患病率远高于西方国家，因为这些人群也经历着严重的营养不良。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Assessment of cholesterol homeostasis in astrocytes and neurons.

评估星形胶质细胞和神经元中的胆固醇稳态。

DOI：
10.1007/978-1-61779-170-3_27
发表时间：
2024-09-13
期刊：
Methods in molecular biology
影响因子：
0
作者：
J. Chen;L. Costa;M. Guizzetti
通讯作者：
M. Guizzetti

Dimethyl fumarate regulates histone deacetylase expression in astrocytes.

富马酸二甲酯调节星形胶质细胞中的组蛋白脱乙酰酶表达。

DOI：
发表时间：
2013-10-15
期刊：
影响因子：
3.3
作者：
Kalinin, Sergey;Polak, Paul E;Lin, Shao Xia;Braun, David;Guizzetti, Marina;Zhang, Xiaolu;Rubinstein, Israel;Feinstein, Douglas L
通讯作者：
Feinstein, Douglas L

Retinoic acid isomers up-regulate ATP binding cassette A1 and G1 and cholesterol efflux in rat astrocytes: implications for their therapeutic and teratogenic effects.

视黄酸异构体上调大鼠星形胶质细胞中的 ATP 结合盒 A1 和 G1 以及胆固醇流出：对其治疗和致畸作用的影响。

DOI：
发表时间：
2011-09
期刊：
影响因子：
0
作者：
Chen, Jing;Costa, Lucio G;Guizzetti, Marina
通讯作者：
Guizzetti, Marina

Prenatal Ethanol Exposure Up-Regulates the Cholesterol Transporters ATP-Binding Cassette A1 and G1 and Reduces Cholesterol Levels in the Developing Rat Brain.

产前乙醇暴露上调胆固醇转运蛋白 ATP 结合盒 A1 和 G1，并降低发育中的大鼠大脑中的胆固醇水平。

DOI：
发表时间：
2014-11
期刊：
影响因子：
0
作者：
Zhou, Chunyan;Chen, Jing;Zhang, Xiaolu;Costa, Lucio G;Guizzetti, Marina
通讯作者：
Guizzetti, Marina

Arylsulfatase B modulates neurite outgrowth via astrocyte chondroitin-4-sulfate: dysregulation by ethanol.

芳基硫酸酯酶 B 通过星形胶质细胞 4-硫酸软骨素调节神经突生长：乙醇引起的失调。

DOI：
发表时间：
2014-02
期刊：
影响因子：
6.2
作者：
Zhang, Xiaolu;Bhattacharyya, Sumit;Kusumo, Handojo;Goodlett, Charles R;Tobacman, Joanne K;Guizzetti, Marina
通讯作者：
Guizzetti, Marina