Ethanol and cholesterol homeostasis in the brain

描述（由申请人提供）：本“探索性/发展性研究资助”（R21）提案将研究乙醇发育性神经毒性的一个新方面，即其对星形胶质细胞胆固醇稳态的影响。过多的胆固醇可能会导致动脉粥样硬化和阿尔茨海默病，而过少的胆固醇则会导致出生缺陷。在有文献记载的先天性胆固醇合成错误（如Smith-Lemli-Opitz综合征）以及母体苯丙酮尿症中，经常观察到不同程度的智力迟钝，苯丙酮尿症的代谢物苯乙酸酯是胆固醇合成的抑制剂。由于这些遗传缺陷，在大脑发育过程中缺乏胆固醇会导致严重的脑损伤，包括小头畸形和智力迟钝，这两种情况都是胎儿酒精综合征的标志。乙醇对发育中的大脑中胆固醇稳态的影响尚未被研究。星形胶质细胞产生大部分用于增殖的脑胆固醇，或者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释放到细胞外，在那里它被神经元吸收并用于树突生长和形成突触。

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.