Ethanol and cholesterol homeostasis in the brain

描述(由申请人提供)：这项“探索性/发展研究资助”(R21)的建议将解决乙醇对发育神经毒性的一个新方面，即它对星形胶质细胞中胆固醇稳态的影响。虽然胆固醇过多可能有害，就像动脉粥样硬化和阿尔茨海默氏症一样，但过少的胆固醇可能会导致出生缺陷。在已有文献记载的先天性胆固醇合成错误中，如Smith-Lemli-Opitz综合征，以及母亲苯丙酮尿症中，经常观察到不同程度的智力发育迟缓，苯乙酸苯酯是胆固醇合成的抑制物。由于这些遗传缺陷，大脑发育期间缺乏胆固醇，除其他外，会导致严重的脑损伤，包括小头畸形和智力低下，这两个都是胎儿酒精综合征的特征。乙醇对发育中大脑中胆固醇稳态的影响还没有被研究过。星形胶质细胞产生大部分用于增殖的脑胆固醇，或通过星形胶质细胞分泌的含有载脂蛋白E的高密度脂蛋白样颗粒在细胞外释放，在细胞外被神经元吸收并用于树突生长和形成突触。 本研究旨在探讨乙醇对大鼠E16、E21和P6星形胶质细胞胆固醇稳态的影响：1.乙醇对胆固醇从头合成和酯化的影响。2.乙醇对胆固醇转运的影响。3.乙醇对载脂蛋白E水平和释放以及对脂蛋白释放和组成的影响。总之，这些研究将为乙醇是否影响星形胶质细胞中的胆固醇稳态提供指示。如果这些终点中的一个或多个受到乙醇的影响，将进行进一步的研究，以更好地了解乙醇影响的机制(S)，并探索这种影响对发育中的大脑的功能后果。

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.