HDACi丁酸钠对精神分裂症表观遗传调节的分子机制研究

发布时间：2018-04-25 01:35

本文选题：精神分裂症 + 表观遗传学　；参考：《吉林大学》2017年硕士论文

【摘要】：精神分裂症是病变表现多样的一种复杂的临床综合症,可表现为观念扭曲,思想混乱,动机削弱,情感缺失等。世界各地观察到的精神分裂症发病率和终身患病率大体相同,世界上约有0.5% 0.8%的人口遭受着精神分裂症的折磨。美国公共精神病医院中约50%的患者为精神分裂症患者,患者人数已超过25万。精神分裂症病情反复且终生不愈,所造成的经济负担对社会和家庭来说都是巨大的。而目前药物治疗对精神分裂症的治疗效果不佳。精神分裂症的发病机理主要是神经递质的转录翻译出现异常,导致脑内神经系统病变,而遗传因素和环境因素均参与了精神分裂症的发病过程,两者交互作用导致精神分裂症的发生。环境因素可能是通过表观遗传修饰致病,表观遗传修饰主要包括DNA甲基化和组蛋白乙酰化。DNA甲基化通过将胞嘧啶变为甲基化胞嘧啶调控基因转录、调节细胞功能。DNA甲基化可导致神经发育障碍,在精神分裂症的发展过程中起到重要作用。DNA甲基化可以被各种因素调节,如社会和环境因素以及化学品和药物等。研究DNA甲基化助于进一步了解疾病的发病过程,更可用于开发治疗疾病的药物。鉴于精神疾病通过表观遗传引起广泛的基因表达变化,许多研究者研究了在精神分裂症和躁郁症中组蛋白乙酰化的作用,它作用于基因表达调控过程中特定基因的启动子,涉及精神分裂症的病理生理过程。重要的是,因为精神分裂症中存在组蛋白乙酰化的改变,所以考虑使用组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitor,HDACi)可能具有减轻精神分裂症症状的临床价值。丁酸钠(Sodium butyrate,butyrate)属于HDACi可引起组蛋白的去乙酰化。体外研究发现丁酸钠在星形胶质细胞中促进BNDF、GDNF的生成,而BDNF对大脑皮层和海马神经元具有保护作用,可以增加神经元的数量,改善神经系统症状和行为模式异常。丁酸钠在小鼠海马齿状回可以明显逆转记忆障碍,促进细胞增殖且降低神经细胞异常分化。因此,本研究选取了与精神分裂症密切相关的9个侯选基因,通过建立精神分裂症表观遗传动物模型,在动物模型中研究各候选基因表达变化,并对大鼠单独或联合应用HDACi butyrate、抗精神病药物氯丙嗪,从而观察butyrate对精神分裂症的作用效果以及是否与氯丙嗪具有协同作用。此外我们还引入了电离辐射,通过对大鼠进行照射观察电离辐射与HDACi的关系。
[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.
【学位授予单位】：吉林大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R749.3

【相似文献】