Ethanol and cholesterol homeostasis in the brain

大脑中的乙醇和胆固醇稳态

• 批准号: 6965973
• 负责人: Marina Guizzetti
• 金额: $ 20.33万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-22 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6965973
• 关键词: apolipoprotein E; astrocytes; brain; cellular pathology; cholesterol; confocal scanning microscopy; cytotoxicity; density gradient ultracentrifugation; developmental disease /disorder; developmental neurobiology; esterification; ethanol; high performance liquid chromatography; homeostasis; immunocytochemistry; laboratory rat; lipid transport; neurotoxins; northern blottings; steroid biosynthesis; thin layer chromatography; tissue /cell culture; western blottings

DESCRIPTION (provided by applicant): This proposal for an "exploratory/developmental research grant" (R21) will address a novel aspect of ethanol's developmental neurotoxicity i.e. its effect on cholesterol homeostasis in astrocytes. While too much cholesterol may be deleterious as in case of atherosclerosis and Alzheimer's disease, too little can engender birth defects. Different degrees of mental retardation are often observed in documented inborn errors of cholesterol synthesis such as Smith-Lemli-Opitz syndrome, as well as in the maternal phenylketonuria, were the accumulating metabolite, phenylacetate, is an inhibitor of cholesterol synthesis. Lack of cholesterol during brain development as a consequence of these genetic defects leads, among others, to severe brain damage including microcephaly and mental retardation, both of which are hallmarks of fetal alcohol syndrome. The effect of ethanol on cholesterol homeostasis in the developing brain has not been investigated. Astrocytes produce most of the brain cholesterol which is used for proliferation or is released, via astrocyte-secreted high density lipoprotein-like particles containing apolipoprotein E, outside the cell where it is taken up and utilized by neurons for dendrite outgrowth and to form synapses. Specific aims of the proposal are to investigate the effects of ethanol on the following aspects of cholesterol homeostasis in rat E16, E21, and P6 astrocytes: 1. The effect of ethanol on the "de novo" synthesis and esterification of cholesterol. 2. The effect of ethanol on cholesterol trafficking. 3. The effect of ethanol on apolipoprotein E levels and release and on lipoprotein release and composition. Altogether these studies will provide indication of whether ethanol affects cholesterol homeostasis in astrocytes. If one or more of these end-points are affected by ethanol, further studies will be directed to better understand the mechanism(s) affected by ethanol and to explore the functional consequences of this effect on the developing brain.

描述（由申请人提供）：“探索/发展研究补助金”（R21）的这一提案将解决乙醇发育神经毒性的新方面，即对星形胶质细胞中胆固醇稳态的影响。尽管在动脉粥样硬化和阿尔茨海默氏病的情况下，胆固醇过多可能是有害的，但几乎没有产生先天缺陷。经常在胆固醇合成的记录的先天误差（例如史密斯 - 莱姆利 - 奥皮茨综合征以及母体苯基酮尿症）中，经常观察到不同程度的智力迟缓。由于这些遗传缺陷，在大脑发育过程中缺乏胆固醇导致严重的脑损伤，包括小头畸形和智力低下，这两者都是胎儿酒精综合征的标志。尚未研究乙醇对发育中大脑中胆固醇稳态的影响。星形胶质细胞产生用于增殖的大部分脑胆固醇，或通过星形胶质细胞分泌的高密度脂蛋白样颗粒释放，含有载脂蛋白E的颗粒，在细胞外，在该细胞中被神经元吸收并利用该细胞，以用于树突生长并形成突触。 该提案的具体目的是研究乙醇对大鼠E16，E21和P6星形胶质细胞中胆固醇稳态以下方面的影响：1。乙醇对胆固醇的“ DE NOK”合成和酯化的影响。 2。乙醇对胆固醇贩运的影响。 3。乙醇对载脂蛋白E水平以及释放以及脂蛋白释放和组成的影响。这些研究总之将表明乙醇是否影响星形胶质细胞中的胆固醇稳态。如果这些终点中的一个或多个受乙醇的影响，则将进一步研究以更好地了解受乙醇影响的机制，并探讨这种影响对发育中大脑的功能后果。