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，从结构异常到功能异常，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) 神经聚糖和短短聚糖构成抑制防止神经突向不正确方向延伸的线索，从而有助于正确的形成的神经元结构。 Neurocan 和 brevican 抑制神经突生长，并且由胶质细胞大量产生细胞，特别是星形胶质细胞，无论是体外还是体内。 CSPG 是由核心蛋白组成的糖蛋白附着在称为硫酸软骨素 (CS) 的糖胺聚糖 (GAG) 线性链上，其组成为 4 硫酸软骨素 (C4S) 和 6 硫酸软骨素 (C6S)； CSPG 的抑制特性取决于其核心蛋白及其GAG链。多种酶参与 GAG 的生物合成和降解链条；芳基硫酸酯酶 B (ARSB) 和半乳糖-6-硫酸酯酶 (GALNS) 可去除 C4S 和 C6S 上的硫酸基分别是 CS-GAG 降解所需的。蒸馏器中 CSPG 的意外增加发育中的大脑可能会导致大脑连接性改变和神经元可塑性过早下降。在这个我们假设乙醇处理的星形胶质细胞通过增加 CSPG 来抑制神经突发生。更多的具体来说，我们假设乙醇通过抑制星形胶质细胞中的 ARSB 和 GALNS 活性，增加这些细胞中的 CS-GAG 和 CSPG 核心蛋白 Neurocan 和 brevican 水平，从而导致抑制海马神经元神经发生。具体目标 1 将研究乙醇对 ARSB 和 GALNS 活性和表达，对 CS-GAG、neurocan 和 brevican 水平的影响，以及对 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细胞发生的抑制。具体目标 2 将研究新生儿体内酒精暴露对 ARSB 和 GALNS 活性的影响，以及蛋白质和 mRNA 表达、CS-GAG、C4S-GAG 以及神经蛋白聚糖和短蛋白聚糖结合的 sGAG 水平，以及海马中的 Neurocan 和 brevican 蛋白和 mRNA 表达。