【摘要】：脆性X綜合征(FXS)為最常見(jiàn)的遺傳性智力低下性疾病之一,是由于FMR1基因異常導(dǎo)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(wú)常等。FMRP是一種mRNA結(jié)合蛋白,可作為翻譯抑制因子負(fù)性調(diào)節(jié)突觸后膜mRNA的翻譯和表達(dá)。研究推測(cè)FMRP缺乏和減少可能導(dǎo)致mGluR激發(fā)的mRNA翻譯增多,異�；钴S的mGluR信號(hào)通路導(dǎo)致神經(jīng)系統(tǒng)發(fā)育的蛋白過(guò)度表達(dá),進(jìn)而影響樹(shù)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(xiàn)為與人類行為相似的社會(huì)交往能力、學(xué)習(xí)和記憶等行為學(xué)的缺陷,模擬出由于FMRP缺失所導(dǎo)致的mGluR信號(hào)過(guò)度表達(dá)的脆性X綜合征疾病表型。 方法：通過(guò)與藥學(xué)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(jìn)行藥物篩選實(shí)驗(yàn),這些藥物包括：JBA、JB1、JB2、JB3、LHP、1gr、MPEP(2-甲基-6-苯基乙炔吡啶)。 結(jié)果：我們發(fā)現(xiàn)JBA藥物對(duì)FX果蠅的社會(huì)交往、立即應(yīng)答和短期記憶缺陷有恢復(fù)作用,JB3藥物對(duì)FX果蠅的立即應(yīng)答和短期記憶缺陷有恢復(fù)作用,JB1藥物對(duì)FX果蠅的社會(huì)交往和立即應(yīng)答缺陷有恢復(fù)作用LHP藥物對(duì)FX果蠅的社會(huì)交往缺陷有恢復(fù)作用,已有報(bào)道的對(duì)FX果蠅的社會(huì)交往、立即應(yīng)答和短期記憶缺陷有恢復(fù)作用的MPEP藥物也在我們的實(shí)驗(yàn)中被驗(yàn)證有恢復(fù)作用。同時(shí),通過(guò)這些藥物篩選到JBA藥物在幼蟲(chóng)和成蟲(chóng)同時(shí)給藥模式下,對(duì)恢復(fù)FX果蠅晝夜節(jié)律缺失現(xiàn)象表現(xiàn)出良好的恢復(fù)作用。 結(jié)論：基于實(shí)驗(yàn)分析我們認(rèn)為最好的mGluR拮抗劑藥物是JBA,通過(guò)比較這些藥物有助于我們確定MPEP有效的分子結(jié)構(gòu),為治療脆性X綜合征提供理論基礎(chǔ)。圖10幅,表1個(gè),參考文獻(xiàn)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(xué)位授予單位】：中南大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R741

【參考文獻(xiàn)】

相關(guān)期刊論文 前2條

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