發(fā)布時間：2018-04-25 01:35

  本文選題：精神分裂癥 + 表觀遺傳學(xué)�。� 參考：《吉林大學(xué)》2017年碩士論文

【摘要】：精神分裂癥是病變表現(xiàn)多樣的一種復(fù)雜的臨床綜合癥,可表現(xiàn)為觀念扭曲,思想混亂,動機(jī)削弱,情感缺失等。世界各地觀察到的精神分裂癥發(fā)病率和終身患病率大體相同,世界上約有0.5% 0.8%的人口遭受著精神分裂癥的折磨。美國公共精神病醫(yī)院中約50%的患者為精神分裂癥患者,患者人數(shù)已超過25萬。精神分裂癥病情反復(fù)且終生不愈,所造成的經(jīng)濟(jì)負(fù)擔(dān)對社會和家庭來說都是巨大的。而目前藥物治療對精神分裂癥的治療效果不佳。精神分裂癥的發(fā)病機(jī)理主要是神經(jīng)遞質(zhì)的轉(zhuǎn)錄翻譯出現(xiàn)異常,導(dǎo)致腦內(nèi)神經(jīng)系統(tǒng)病變,而遺傳因素和環(huán)境因素均參與了精神分裂癥的發(fā)病過程,兩者交互作用導(dǎo)致精神分裂癥的發(fā)生。環(huán)境因素可能是通過表觀遺傳修飾致病,表觀遺傳修飾主要包括DNA甲基化和組蛋白乙�；�。DNA甲基化通過將胞嘧啶變?yōu)榧谆奏ふ{(diào)控基因轉(zhuǎn)錄、調(diào)節(jié)細(xì)胞功能。DNA甲基化可導(dǎo)致神經(jīng)發(fā)育障礙,在精神分裂癥的發(fā)展過程中起到重要作用。DNA甲基化可以被各種因素調(diào)節(jié),如社會和環(huán)境因素以及化學(xué)品和藥物等。研究DNA甲基化助于進(jìn)一步了解疾病的發(fā)病過程,更可用于開發(fā)治療疾病的藥物。鑒于精神疾病通過表觀遺傳引起廣泛的基因表達(dá)變化,許多研究者研究了在精神分裂癥和躁郁癥中組蛋白乙�；淖饔�,它作用于基因表達(dá)調(diào)控過程中特定基因的啟動子,涉及精神分裂癥的病理生理過程。重要的是,因為精神分裂癥中存在組蛋白乙�；母淖�,所以考慮使用組蛋白去乙酰化酶抑制劑(histone deacetylase inhibitor,HDACi)可能具有減輕精神分裂癥癥狀的臨床價值。丁酸鈉(Sodium butyrate,butyrate)屬于HDACi可引起組蛋白的去乙�；�。體外研究發(fā)現(xiàn)丁酸鈉在星形膠質(zhì)細(xì)胞中促進(jìn)BNDF、GDNF的生成,而BDNF對大腦皮層和海馬神經(jīng)元具有保護(hù)作用,可以增加神經(jīng)元的數(shù)量,改善神經(jīng)系統(tǒng)癥狀和行為模式異常。丁酸鈉在小鼠海馬齒狀回可以明顯逆轉(zhuǎn)記憶障礙,促進(jìn)細(xì)胞增殖且降低神經(jīng)細(xì)胞異常分化。因此,本研究選取了與精神分裂癥密切相關(guān)的9個侯選基因,通過建立精神分裂癥表觀遺傳動物模型,在動物模型中研究各候選基因表達(dá)變化,并對大鼠單獨或聯(lián)合應(yīng)用HDACi butyrate、抗精神病藥物氯丙嗪,從而觀察butyrate對精神分裂癥的作用效果以及是否與氯丙嗪具有協(xié)同作用。此外我們還引入了電離輻射,通過對大鼠進(jìn)行照射觀察電離輻射與HDACi的關(guān)系。
[Abstract]:Schizophrenia is a complicated clinical syndrome with various pathological manifestations, which can be characterized by distorted ideas, confusion of thought, weakening of motivation and lack of emotion. The incidence and lifetime prevalence of schizophrenia are almost the same all over the world, and about 0.5% or 0.8% of the world's population suffer from schizophrenia. About 50 per cent of patients in public psychiatric hospitals in the United States are schizophrenics, with more than 250000 patients. The financial burden of schizophrenia is enormous for both society and families. At present, the effect of drug therapy on schizophrenia is not good. The pathogenesis of schizophrenia is mainly due to abnormal transcription translation of neurotransmitters, which leads to neuropathy in the brain. Both genetic and environmental factors are involved in the pathogenesis of schizophrenia. The interaction between the two causes schizophrenia. Environmental factors may be caused by epigenetic modification, which mainly includes DNA methylation and histone acetylation. DNA methylation regulates gene transcription by transforming cytosine into methylated cytosine. Regulation of cell function. DNA methylation can lead to neurodevelopmental disorders. DNA methylation plays an important role in the development of schizophrenia. DNA methylation can be regulated by various factors, such as social and environmental factors, chemicals and drugs. The study of DNA methylation helps to further understand the pathogenesis of disease and can be used to develop drugs for the treatment of disease. Since mental disorders cause extensive changes in gene expression through epigenetics, many researchers have studied the role of histone acetylation in schizophrenia and bipolar disorder, which act as promoters of specific genes in the regulation of gene expression. The pathophysiological process involved in schizophrenia. It is important that, because histone acetylation is present in schizophrenia, consideration of histone deacetylase inhibitor HDA Cii may have a clinical value in alleviating schizophrenia symptoms. Sodium butyratebutyrate (HDACi) can induce deacetylation of histone. In vitro, it was found that sodium butyrate promoted the production of GDNF in astrocytes, while BDNF had protective effects on cerebral cortex and hippocampal neurons, which could increase the number of neurons and improve the symptoms and behavioral patterns of nervous system. Sodium butyrate in mouse dentate gyrus could reverse memory impairment, promote cell proliferation and decrease abnormal differentiation of neurons. Therefore, 9 candidate genes closely related to schizophrenia were selected in this study, and the expression of candidate genes was studied in the animal model by establishing an epigenetic animal model of schizophrenia. HDACi butyrate and chlorpromazine were used alone or in combination to observe the effect of butyrate on schizophrenia and whether it had synergistic effect with chlorpromazine. In addition, ionizing radiation was introduced to observe the relationship between ionizing radiation and HDACi in rats.
【學(xué)位授予單位】：吉林大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R749.3

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本文編號：1799197