ALCOHOL EFFECTS ON GANGLIOSIDE DEPENDENT NEUROGENESIS

酒精对神经节苷脂依赖性神经发生的影响

• 批准号: 2045922
• 负责人: ABRAHAM ROSENBERG
• 金额: $ 10万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-01 至 1996-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2045922
• 关键词: embryo /fetus toxicology; ethanol; gangliosides; neurogenesis

This is a Shannon Award providing partial support for the research projects that fall short of the assigned institute's funding range but are in the margin of excellence. The Shannon Award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. The abstract below is taken from the original document submitted by the principal investigator. Neuritogenesis governs developmental migration, axonogenesis and dendritic arborization of neurons, CNS phenomena which are aberrant in experimental FAS. Neuritogenesis depends mechanistically upon 1) plasma membrane-substratum adhesion and 2) neurital plasma membrane extension. The simple gangliosides G-M3 and G-D3 promote plasma membrane integrin- regulated and carbohydrate shear-modulated substrate adhesion. Syntheses of G-M3/G-D3 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 G-M3/G- D3. Chronic exposure of cells to ethanol reduces EGF-receptor (EGFR) endocytosis, thus limiting endosomal G-M3/G-D3 re-tailoring, and weakening adhesion loci. The effects of chronic ethanol exposure on G- M3/G-D3 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 G-T1b, G-Q1b. Attenuated neuritogenesis results from inhibition of cytoskeletally regulated anterograde Golgi biosynthesis of G-T1b, G-Q1b. 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 block gangliosides (G-T1B/G-Q1b) in neurite preservation A) in neuron culture and B) in vivo in embryonic chick brain, during chronic exposure to ethanol.

这是一个香农奖提供部分支持的研究 项目不属于指定的研究所的资金范围，但 都处于优秀的边缘。 香农奖旨在 提供支持，以测试该方法的可行性;进一步发展 测试和完善研究技术;进行二次分析 可用的数据集;或进行离散项目， PI的研究能力或为已经存在的 有价值的申请。 下面的摘要摘自原文 主要研究者提交的文件。 神经发生支配着发育迁移、轴突发生和 神经元的树突状分支，中枢神经系统的现象，这是异常的， 实验FAS。 神经发生机制上依赖于1）血浆 膜-基质粘附; 2）轴突质膜延伸。 简单的神经节苷脂G-M3和G-D3促进质膜整合素- 调节和碳水化合物剪切调节的底物粘附。 合成 G-M3/G-D3通过IC-高尔基体衍生的外表面（外）唾液酸转移酶 在EGF诱导的再循环内体中重新定位， EGF诱导的内吞作用，可能是一种独特的神经机制，促进 粘附，通过产生质膜G-M3/G- D3. 细胞长期暴露于乙醇会降低EGF受体（EGFR） 内吞作用，从而限制了内体G-M3/G-D3重新剪裁，以及 减弱粘附位点。 慢性乙醇暴露对G- EGFR诱导的内体中的M3/G-D3唾液酸化将在两种细胞中定量。 鸡神经元培养物和卵内FAS模型。 神经突质膜延伸需要添加到血浆中 高尔基体衍生的质膜元件的膜具有非常高的 促神经突的结构含量（末端唾液酸化 神经节四糖基神经酰胺）神经节苷脂糖型，特别是主要的 神经节苷脂G-T1 b、G-Q1 b。 神经突生成减弱的原因是 抑制细胞内调节的顺行高尔基体生物合成 G-T1b G-Q1b 剂量和时间依赖性慢性乙醇诱导抑制 在神经元培养中这些神经节苷脂的生物合成， 将使用[3 H]ManNAc对卵内全胚胎FAS模型进行追踪， 专性唾液酸前体。 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： 外源性再供应神经元质膜与积木 神经节苷脂（G-T1 B/G-Q1 b）在神经突保存中的作用A）在神经元培养中 和B）在体内，在长期暴露于 乙醇