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.

乙醇对发展中的大脑产生深远影响，从结构异常到功能异常，导致胎儿酒精的认知和行为功能受损频谱障碍（FASD）。神经元成熟是神经发展的重要过程系统。脑特异性软骨素硫酸盐蛋白聚糖（CSPGS）Neurocan和Brevican构成抑制提示阻止神经突在不当方向上扩展的提示，因此有助于适当的形成神经元建筑。 Neurocan和Brevican抑制神经突生长，并高度通过神经胶质产生细胞，尤其是体内和体内的星形胶质细胞。 CSPG是由核蛋白组成的糖蛋白附着在称为软骨素硫酸盐（CS）的糖胺聚糖（GAGS）的线性链上，其中包括软骨素-4硫酸盐（C4S）和软骨素6硫酸盐（C6S）； CSPG的抑制特性取决于它们核蛋白及其插科打链。几种酶参与了GAG的生物合成和降解链芳基硫酸蛋白酶B（ARSB）和半乳糖-6-硫酸酯酶（GALNS）从C4和C6S中去除硫酸盐基团分别是CS-GAG降解所必需的。静止中的CSPG的外观不习惯增加发展大脑可能会导致大脑连通性的改变，并导致神经元可塑性的过度降低。在这个建议我们假设乙醇处理的星形胶质细胞通过增加CSPG抑制神经发生。更多的具体而言，我们假设乙醇是通过抑制星形胶质细胞中ARSB和GALNS活性的，在这些细胞中增加CS-GAG和CSPG核蛋白神经蛋白和Brevican水平，导致抑制作用海马神经元神经发生。具体目标1将研究乙醇对ARSB的影响 galns的活性和表达，对CS-GAG，神经群和Brevican水平，以及ARSB和ARSB的作用 galns在调节乙醇诱导的体外抑制星形胶质细胞介导的海马神经发生。具体目标2将研究体内新生儿酒精暴露对ARSB和GALNS活性的影响以及蛋白质和mRNA表达，CS-GAG，C4S-GAG以及神经群和Brevican结合的SGAG水平，以及海马中的神经胶质和Brevican蛋白以及mRNA表达。