权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

ALCOHOL EFFECTS ON GANGLIOSIDE DEPENDENT NEUROGENESIS

酒精对神经节苷脂依赖性神经发生的影响

基本信息

批准号：
2413247
负责人：
ABRAHAM ROSENBERG
金额：
$ 14.62万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-09-01 至 1999-04-30
项目状态：
已结题

项目摘要

Neuritogenesis governs developmental migration, axonogenesis and dendritic arborization of neurons, CNS phenomena which are aberrant in: experimental FAS. Neuritogenesis depends mechanistically upon l) plasma membrane- substratum adhesion and 2) neurital plasma membrane extension. The simple gangliosides GM3 and GD3 promote plasma membrane integrin-regulated and carbohydrate shear-modulated substrate adhesion. Synthesis of GM3/GD3 by IC-Golgi derived exofacial (ecto) sialyl transferases relocated within EGF-induced recycling endosomes, which are formed by EGF-induced endocytosis, may be a unique neuronal mechanism for promoting adhesion, by producing targeted localization of plasma membrane GM3/GD3. Chronic exposure of cells to ethanol reduces EGF-receptor (EGFR) endocytosis, thus limiting endosomal GM3/GD3 re-tailoring, and weakening adhesion loci. The effects of chronic ethanol exposure on GM3/GD3 sialylation in EGFR-induced endosomes will be quantitated in both a chick neuron culture and in an in ovo FAS model. Neurite plasma membrane extension requires addition to the plasma membrane of Golgi-derived plasma membrane elements with a very high structural content of neuritogenic (terminally-sialylated gangliotetraosyl ceramide) ganglioside glycoforms, particularly the major gangliosides GT1b, GQ1b Attenuated neuritogenesis results from inhibition of cytoskeletally regulated anterograde Golgi biosynthesis of GT1B, GQ1b. Dose-and time- dependent chronic ethanol-induced inhibition of biosynthesis of these gangliosides in neuron culture and a parallel whole embryo in ovo FAS model will be traced with [3H)ManNAc, as an obligate sialic acid precursor. Vulnerability of the differentiating embryonic CNS neuron to chronic ethanol-induced biosynthetic inhibition of sialylation of key neuronal gangliosides will be documented in detail. Evaluation will be made of exogenous re-supply of the neurital plasma membrane with building black gangliosides (GT1b/GQ1b) in neurite preservation A) in neuron culture and B) in vivo in embryonic chick brain, during chronic exposure to ethanol.

神经发生支配发育迁移、轴突发生和树突状细胞神经元树枝状化，中枢神经系统异常现象：实验 FAS。神经发生在机制上依赖于l）质膜- 基质粘附; 2）神经突质膜延伸。简单神经节苷脂GM 3和GD 3促进质膜整合素调节，碳水化合物剪切调节基底粘附。GM 3/GD 3的合成 IC-高尔基体衍生的外表面（外）唾液酸转移酶在 EGF诱导的再循环内体，其由EGF诱导的内吞作用，可能是一种独特的神经机制，促进粘附，产生质膜GM 3/GD 3的靶向定位。慢性细胞暴露于乙醇减少EGF受体（EGFR）的内吞作用，因此限制了内体GM 3/GD 3重新剪裁，并削弱了粘附位点。的慢性乙醇暴露对EGFR诱导的人肝癌细胞GM 3/GD 3唾液酸化的影响将在鸡神经元培养物和在神经细胞培养物中定量内体。卵FAS模型。神经突质膜延伸需要添加到质膜高尔基体衍生的质膜元件具有非常高的结构神经突原（末端唾液酸化神经节四糖基神经酰胺）含量神经节苷脂糖型，特别是主要的神经节苷脂GT 1b、GQ 1b 神经突发生减弱是由于细胞增殖抑制调节GT 1B、GQ 1b的顺行高尔基体生物合成。剂量和时间依赖性慢性乙醇诱导的这些生物合成的抑制神经元培养中的神经节苷脂和平行的卵内全胚胎FAS 模型将用[3 H] ManNAc作为专性唾液酸进行追踪先驱分化中的胚胎中枢神经系统神经元对慢性乙醇诱导的关键神经元唾液酸化的生物合成抑制将详细记录神经节苷脂。将对以下方面进行评价：用建筑黑对轴突质膜进行外源性再供应神经节苷脂（GT 1b/GQ 1b）在神经突保存中的作用A）在神经元培养中的作用， B）在体内，在长期暴露于乙醇的过程中，在鸡胚脑中。