新型mGluR拮抗剂对脆性X果蝇模型的改善作用

发布时间：2018-10-10 11:20

【摘要】：脆性X综合征(FXS)为最常见的遗传性智力低下性疾病之一,是由于FMR1基因异常导致其编码的脆性X智力低下蛋白减少或缺失所致,伴随着一些明显的临床症状如白闭症、精神发育迟缓和睡眠无常等。FMRP是一种mRNA结合蛋白,可作为翻译抑制因子负性调节突触后膜mRNA的翻译和表达。研究推测FMRP缺乏和减少可能导致mGluR激发的mRNA翻译增多,异常活跃的mGluR信号通路导致神经系统发育的蛋白过度表达,进而影响树突棘的发育。目的：利用脆性X果蝇模型(FX),基于dfmr1基因的失活表现为与人类行为相似的社会交往能力、学习和记忆等行为学的缺陷,模拟出由于FMRP缺失所导致的mGluR信号过度表达的脆性X综合征疾病表型。方法：通过与药学院合作从天然植物提取物中提取几种mG1uR拮抗剂药物,在FX果蝇模型中进行药物筛选实验,这些药物包括：JBA、JB1、JB2、JB3、LHP、1gr、MPEP(2-甲基-6-苯基乙炔吡啶)。结果：我们发现JBA药物对FX果蝇的社会交往、立即应答和短期记忆缺陷有恢复作用,JB3药物对FX果蝇的立即应答和短期记忆缺陷有恢复作用,JB1药物对FX果蝇的社会交往和立即应答缺陷有恢复作用LHP药物对FX果蝇的社会交往缺陷有恢复作用,已有报道的对FX果蝇的社会交往、立即应答和短期记忆缺陷有恢复作用的MPEP药物也在我们的实验中被验证有恢复作用。同时,通过这些药物筛选到JBA药物在幼虫和成虫同时给药模式下,对恢复FX果蝇昼夜节律缺失现象表现出良好的恢复作用。结论：基于实验分析我们认为最好的mGluR拮抗剂药物是JBA,通过比较这些药物有助于我们确定MPEP有效的分子结构,为治疗脆性X综合征提供理论基础。图10幅,表1个,参考文献83篇。
[Abstract]:Fragile X syndrome (FXS) is one of the most common hereditary mental retardation diseases. It is caused by the decrease or deletion of fragile X mental retardation protein encoded by the abnormal FMR1 gene. Mental retardation and sleep impermanence. FMRP is a mRNA binding protein that acts as a translation suppressor to negatively regulate the translation and expression of postsynaptic membrane mRNA. It is speculated that the deficiency and decrease of FMRP may lead to the increase of mRNA translation stimulated by mGluR, and the hyperactive mGluR signaling pathway may lead to the overexpression of proteins in nervous system development, and then affect the development of dendritic spine. Objective: the inactivation of (FX), based on dfmr1 gene in a fragile X Drosophila model was characterized by behavioral deficits such as social interaction, learning and memory similar to human behavior. The disease phenotypes of fragile X syndrome caused by FMRP deletion and overexpression of mGluR signal were simulated. Methods: several mG1uR antagonists were extracted from natural plant extracts in collaboration with the Pharmacology Institute, and the drug screening experiments were carried out in the FX Drosophila model. These drugs included JB _ (1) (JB _ (2) and JB _ (3) LHP _ (1) GRP (2-methyl-6-phenyleacetylpyridine) (MPEP) in Drosophila melanogaster (Drosophila melanogaster) model. Results: we found that the social interaction of JBA drugs on FX flies, Immediate response and short term memory impairment have recovery effects on the immediate response and short term memory impairment of FX Drosophila. JB1 has a recovery effect on social interaction and immediate response deficiency of FX Drosophila FX. LHP drugs have a recovery effect on FX fruit. The social interaction defects of flies have a recovery effect. MPEP drugs, which have been reported to restore the social interaction, immediate response and short term memory impairment of FX Drosophila, have also been shown to have a restorative effect in our experiments. At the same time, through the screening of these drugs, JBA showed a good effect on restoring the diurnal rhythm deficiency of FX Drosophila under the pattern of larval and adult administration simultaneously. Conclusion: based on the experimental analysis, we think that the best mGluR antagonist is JBA,. Comparing these drugs can help us to determine the effective molecular structure of MPEP and provide a theoretical basis for the treatment of fragile X syndrome. Ten figures, one table, 83 references.
【学位授予单位】：中南大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R741

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