【摘要】：脆性X綜合征(FXS)為最常見的遺傳性智力低下性疾病之一,是由于FMR1基因異常導致其編碼的脆性X智力低下蛋白減少或缺失所致,伴隨著一些明顯的臨床癥狀如白閉癥、精神發(fā)育遲緩和睡眠無常等。FMRP是一種mRNA結合蛋白,可作為翻譯抑制因子負性調節(jié)突觸后膜mRNA的翻譯和表達。研究推測FMRP缺乏和減少可能導致mGluR激發(fā)的mRNA翻譯增多,異�；钴S的mGluR信號通路導致神經系統發(fā)育的蛋白過度表達,進而影響樹突棘的發(fā)育。 目的：利用脆性X果蠅模型(FX),基于dfmr1基因的失活表現為與人類行為相似的社會交往能力、學習和記憶等行為學的缺陷,模擬出由于FMRP缺失所導致的mGluR信號過度表達的脆性X綜合征疾病表型。 方法：通過與藥學院合作從天然植物提取物中提取幾種mG1uR拮抗劑藥物,在FX果蠅模型中進行藥物篩選實驗,這些藥物包括：JBA、JB1、JB2、JB3、LHP、1gr、MPEP(2-甲基-6-苯基乙炔吡啶)。 結果：我們發(fā)現JBA藥物對FX果蠅的社會交往、立即應答和短期記憶缺陷有恢復作用,JB3藥物對FX果蠅的立即應答和短期記憶缺陷有恢復作用,JB1藥物對FX果蠅的社會交往和立即應答缺陷有恢復作用LHP藥物對FX果蠅的社會交往缺陷有恢復作用,已有報道的對FX果蠅的社會交往、立即應答和短期記憶缺陷有恢復作用的MPEP藥物也在我們的實驗中被驗證有恢復作用。同時,通過這些藥物篩選到JBA藥物在幼蟲和成蟲同時給藥模式下,對恢復FX果蠅晝夜節(jié)律缺失現象表現出良好的恢復作用。 結論：基于實驗分析我們認為最好的mGluR拮抗劑藥物是JBA,通過比較這些藥物有助于我們確定MPEP有效的分子結構,為治療脆性X綜合征提供理論基礎。圖10幅,表1個,參考文獻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.
【學位授予單位】：中南大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R741

【參考文獻】

相關期刊論文 前2條

1 董玉霞;孫曉紅;宋衛(wèi)科;何悅;;脆性X智力低下蛋白致病機制研究進展[J];中國現代神經疾病雜志;2010年03期

2 李東至,廖燦;脆性X綜合征[J];中國優(yōu)生與遺傳雜志;2005年05期

，

本文編號：2261572