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

Effect of ethanol on chondroitin sulfate proteoglycans: relevance to FASD

乙醇对硫酸软骨素蛋白聚糖的影响：与 FASD 的相关性

基本信息

批准号：
8635044
负责人：
Marina Guizzetti
金额：
$ 22.93万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-05 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8635044
关键词：
Adopted Affect Alcohols Anabolism Architecture Arylsulfatase B Astrocytes Attenuated Axon Behavioral Binding Biology Brain Brain region CSPG3 gene Cells Characteristics Chondroitin Sulfate A Chondroitin Sulfate C Chondroitin Sulfate Proteoglycan Chondroitin Sulfates Coculture Techniques Cognitive Commissure Core Protein Corpus Callosum Cues Dendrites Development Enzymes Ethanol Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Future Galactose Glycobiology Glycoproteins Glycosaminoglycan Degradation Pathway Glycosaminoglycans Hippocampus (Brain)Human In Vitro Inorganic Sulfates Intervention Lead Mediating Messenger RNA Modeling Neonatal Neonatal Alcohol Exposure Neurites Neuroglia Neuronal Plasticity Neurons Pregnancy Process Property Proteins Rattus Recombinants Reporting Research Role Signal Transduction Sulfatases Supplementation Synapses Testing Third Pregnancy Trimester Time Unspecified or Sulfate Ion Sulfates Up-Regulation Visual system structure alcohol effect alcohol exposure base brain commissure brevican cellular targeting chondroitin sulfate glycosaminoglycan design in vivo innovation mRNA Expression nervous system development novel polysulfated glycosaminoglycan premature prevent protein expression proteoglycan core protein public health relevance treatment effect

项目摘要

Ethanol exerts profound effects on the developing brain, which range from structural abnormalities to functional anomalies, resulting in compromised cognitive and behavioral functions characteristic of fetal alcohol spectrum disorders (FASD). Neuronal maturation is an essential process in the development of the nervous system. Brain-specific chondroitin sulfate proteoglycans (CSPGs) neurocan and brevican constitute inhibitory cues that prevent the extension of neurites in improper directions therefore contributing to the proper formation of neuronal architecture. Neurocan and brevican inhibit neurite outgrowth and are highly produced by glial cells, and astrocytes in particular, both in vitro and in vivo. CSPG are glycoproteins consisting of core-proteins attached to linear chains of glycosaminoglycans (GAGs) called chondroitin sulfates (CS), which consists in chondroitin-4 sulfate (C4S) and chondroitin-6 sulfate (C6S); the inhibitory properties of CSPGs depend on their core-protein and their GAG chains. Several enzymes are involved in the biosynthesis and degradation of GAG chains; arylsulfatase B (ARSB) and galactose-6-sulfatase (GALNS) remove sulfate groups from C4S and C6S respectively and are required for the degradation of CS-GAGs. An unscheduled increase in CSPGs in the still developing brain may lead to altered brain connectivity and to premature decrease in neuronal plasticity. In this proposal we hypothesize that ethanol-treated astrocytes inhibits neuritogenesis by increasing CSPGs. More specifically, we hypothesize that ethanol, through the inhibition of ARSB and GALNS activity in astrocytes, increases CS-GAG and CSPG core-protein neurocan and brevican levels in these cells leading to the inhibition of hippocampal neuron neuritogenesis. Specific aim 1 will investigate the effect of ethanol on ARSB and GALNS activity and expression, on CS-GAG, neurocan, and brevican levels, and on the role of ARSB and GALNS in modulating ethanol-induced inhibition of astrocyte-mediated hippocampal neuritogenesis in vitro. Specific Aim 2 will investigate the effect of in vivo neonatal alcohol exposure on ARSB and GALNS activity and protein and mRNA expression, CS-GAG, C4S-GAG, and neurocan- and brevican-bound sGAG levels, and neurocan and brevican protein and mRNA expression in the hippocampus.

乙醇对发育中的大脑产生深远的影响，包括结构异常，功能异常，导致胎儿酒精特征的认知和行为功能受损谱系障碍（FASD）。神经元成熟是神经发育的重要过程，系统脑特异性硫酸软骨素蛋白聚糖（CSPG）神经聚糖和短蛋白聚糖构成抑制性阻止神经突向不正确方向延伸的线索因此有助于正确的形成神经元结构。Neurocan和Brevican抑制神经突生长，并且由神经胶质细胞高度产生。细胞，特别是星形胶质细胞，在体外和体内。CSPG是由核心蛋白组成的糖蛋白连接到称为硫酸软骨素（CS）的糖胺聚糖（GAG）的线性链上，其包括：硫酸软骨素-4（C4 S）和硫酸软骨素-6（C6 S）; CSPG的抑制特性取决于它们的核心蛋白及其GAG链。几种酶参与GAG的生物合成和降解芳基硫酸酯酶B（ARSB）和半乳糖-6-硫酸酯酶（GALNS）从C4 S和C6 S上除去硫酸酯基团并且是CS-GAG降解所需的。蒸馏器中CSPG的计划外增加发育中的大脑可能导致改变的大脑连接性和神经元可塑性的过早降低。在这我们假设乙醇处理的星形胶质细胞通过增加CSPGs抑制轴突发生。更具体地说，我们假设乙醇通过抑制星形胶质细胞中ARSB和GALNS活性，增加这些细胞中CS-GAG和CSPG核心蛋白神经聚糖和短蛋白聚糖的水平，导致抑制海马神经元轴突发生的过程。具体目标1将研究乙醇对ARSB的影响， GALNS活性和表达，CS-GAG、神经聚糖和短蛋白聚糖水平，以及ARSB和 GALNS在体外调节乙醇诱导的星形胶质细胞介导的海马神经突发生抑制。具体目标2将研究体内新生儿酒精暴露对ARSB和GALNS活性的影响，蛋白质和mRNA表达、CS-GAG、C4 S-GAG以及神经聚糖和短聚糖结合的sGAG水平，以及海马中neurocan和brevican蛋白和mRNA的表达。