慢性不可預(yù)見(jiàn)性應(yīng)激抑郁模型大鼠海馬MKP-1表達(dá)及其啟動(dòng)子區(qū)組蛋白H3乙�；癄顟B(tài)研究
發(fā)布時(shí)間：2019-06-04 22:52
【摘要】：背景 抑郁障礙以心境低落為主要臨床特征,具有明顯慢性化傾向,嚴(yán)重影響患者的身心健康,造成沉重的疾病負(fù)擔(dān)。對(duì)抑郁障礙分子生物學(xué)機(jī)制的了解有助于改進(jìn)治療方法,改善預(yù)后。近年來(lái),相關(guān)研究中,細(xì)胞內(nèi)信號(hào)系統(tǒng)逐漸受到人們的重視,越來(lái)越多的研究發(fā)現(xiàn),決定神經(jīng)元增殖、分化、成熟、存活、突起生長(zhǎng)等的細(xì)胞內(nèi)信號(hào)通路與抑郁障礙密切相關(guān)。MAPK信號(hào)系統(tǒng)位于胞內(nèi),可傳導(dǎo)多種細(xì)胞外信號(hào)至細(xì)胞內(nèi),引起基因的表達(dá)的變化,此系統(tǒng)在中樞神經(jīng)系統(tǒng)中的活性與抑郁密切相關(guān)。有研究提示,作為MAPK系統(tǒng)的負(fù)性調(diào)節(jié)因子之一,腦中MKP-1的過(guò)表達(dá)可能與抑郁的發(fā)生相關(guān)。作為表觀遺傳學(xué)修飾機(jī)制之一,啟動(dòng)子區(qū)組蛋白H3乙�；梢鸹虮磉_(dá)的提高,推測(cè)MKP-1啟動(dòng)子區(qū)組蛋白H3乙酰化修飾也可能參與抑郁的發(fā)生。本研究建立大鼠慢性不可預(yù)見(jiàn)性應(yīng)激抑郁模型,以氟西汀為干預(yù)藥物,以海馬為研究目標(biāo)腦區(qū),探討MKP-1表達(dá)及其啟動(dòng)子區(qū)組蛋白H3乙酰化在抑郁障礙發(fā)生中的地位。 目的 1.了解海馬區(qū)MKP-1表達(dá)及其啟動(dòng)子區(qū)組蛋白乙�；癄顟B(tài)與抑郁模型大鼠類抑郁樣表現(xiàn)的關(guān)系。 2.了解氟西汀抗抑郁效應(yīng)與海馬區(qū)MKP-1表達(dá)及其啟動(dòng)子區(qū)組蛋白乙酰化狀態(tài)的關(guān)系。 方法 1.實(shí)驗(yàn)動(dòng)物,分組,及抑郁模型的建立 將行為學(xué)評(píng)價(jià)得分相近的30只SD大鼠隨機(jī)平均分為3組,對(duì)照組(control),刺激組(CUS),刺激+氟西汀組(CUS+fluoxetine)。對(duì)照組正常飼養(yǎng),其余2組給予慢性不可預(yù)見(jiàn)性應(yīng)激共實(shí)施42天,制備抑郁模型。 2.藥物干預(yù)方法 干預(yù)藥物采用氟西汀,模擬患者給藥途徑,用灌胃法給藥。刺激組給予相同容積的生理鹽水灌胃模擬藥物干預(yù)。 3.行為學(xué)評(píng)價(jià)方法 采用體質(zhì)量變化、曠場(chǎng)試驗(yàn)、蔗糖水消耗試驗(yàn)對(duì)大鼠進(jìn)行行為學(xué)評(píng)價(jià)。 4.實(shí)驗(yàn)室方法 采用免疫組化法了解海馬MKP-1蛋白表達(dá)狀態(tài),采用染色質(zhì)免疫共沉淀(CHIP)法了解組蛋白乙�；癄顟B(tài)。 5.統(tǒng)計(jì)學(xué)方法 采用方差分析分析實(shí)驗(yàn)數(shù)據(jù),用SPSS13.0進(jìn)行數(shù)據(jù)處理。采用單因素方差分析(one-way ANOVA)進(jìn)行比較。以P0.05為差異有統(tǒng)計(jì)學(xué)意義。 結(jié)果 1.行為學(xué)評(píng)價(jià) 實(shí)驗(yàn)前,各組大鼠的體質(zhì)量、水平運(yùn)動(dòng)距離、蔗糖水消耗比例差異無(wú)統(tǒng)計(jì)學(xué)意義(P=0.699,P=0.950,P=0.996)。慢性應(yīng)激21天后,體質(zhì)量、水平運(yùn)動(dòng)距離、蔗糖水消耗比例刺激組(P=0.003,P=0.013,P=0.009)、刺激+氟西汀組(P=0.000,P=0.022,P=0.008)較對(duì)照組明顯下降。藥物干預(yù)21天后,刺激組體質(zhì)量、水平運(yùn)動(dòng)距離、蔗糖水消耗比例顯著低于對(duì)照組(P=0.000,P=0.001,P=0.000)；刺激+氟西汀組水平運(yùn)動(dòng)距離、蔗糖水消耗比例較刺激組明顯提高(P=0.000,P=0.000)；刺激+氟西汀組和對(duì)照組比較差異無(wú)統(tǒng)計(jì)學(xué)意義(P=0.663,P=0.087)；體質(zhì)量刺激組和刺激+氟西汀組低于對(duì)照組,差異有計(jì)學(xué)意義(P=0.000,P=0.000)。 2.模型大鼠海馬MKP-1表達(dá)以及氟西汀的作用 刺激組海馬CA1、CA3、DG區(qū)MKP-1表達(dá)較對(duì)照組明顯提高,差異有統(tǒng)計(jì)學(xué)意義(P=0.000,P=0.000,P=0.000)。刺激+氟西汀組海馬CA1、CA3、DG區(qū)MKP-1表達(dá)較刺激組明顯下降,差異有統(tǒng)計(jì)學(xué)意義(P=0.002,P=0.009,P=0.000)。各組大鼠海馬CA2區(qū)MKP-1表達(dá)差異無(wú)統(tǒng)計(jì)學(xué)意義(P=0.828)。 3.模型大鼠海馬MKP-1啟動(dòng)子區(qū)組蛋白H3乙酰化情況及氟西汀的作用 刺激組海馬MKP-1啟動(dòng)子區(qū)組蛋白H3乙�；潭容^對(duì)照組明顯提高,差異有統(tǒng)計(jì)學(xué)意義(P=0.004)。刺激+氟西汀組較刺激組無(wú)明顯下降,差異無(wú)統(tǒng)計(jì)學(xué)意義(P=0.323)。刺激+氟西汀組高于對(duì)照組,差異有統(tǒng)計(jì)學(xué)意義(P=0.037)。 結(jié)論 1.慢性不可預(yù)見(jiàn)性應(yīng)激抑郁模型大鼠海馬內(nèi)MKP-1表達(dá)升高與啟動(dòng)子區(qū)組蛋白H3乙�；缴�,可能參與抑郁癥的發(fā)病機(jī)制。 2.氟西汀能改善抑郁模型大鼠的行為表現(xiàn)并逆轉(zhuǎn)海馬內(nèi)MKP-1過(guò)表達(dá),可能是氟西汀抗抑郁機(jī)制的靶點(diǎn)之一。
[Abstract]:background Depressive disorder is the main clinical characteristic of depression, which has the obvious chronic tendency, which seriously affects the physical and mental health of the patient, and causes the heavy disease to be negative The understanding of molecular biological mechanisms in the disorder of depression can help to improve the methods of treatment and to improve the pre-treatment In recent years, in recent years, in the relevant research, the signal system in the cell is gradually being paid attention to, and more and more research has found that the signal pathway in the cells, such as neuron proliferation, differentiation, maturation, survival, protrusion growth, and the like, is closely related to the depressive disorder. The MAPK signal system is located in the cell, can conduct various extracellular signals to the cell, cause the change of the expression of the gene, and the activity of the system in the central nervous system is closely related to the depression The results suggest that the overexpression of MKP-1 in the brain may be associated with the occurrence of depression as one of the negative regulation factors of the MAPK system. On the other hand, as one of the epigenetic modification mechanisms, the histone H3 ethylation of the promoter region can cause the increase of gene expression, and it is presumed that the histone H3 ethylation modification of the MKP-1 promoter region may also be involved in the development of depression. To study the relationship between the expression of MKP-1 and the histone H3 of its promoter region in the pathogenesis of depression. Bit. Objective: To study the expression of MKP-1 in hippocampus and the depression pattern of histone in the model of depression. 2. To study the effect of fluoxetine on the expression of MKP-1 in hippocampus and its promoter region histone B systematize A state-to-state relationship. Method 1. Experimental animals Thirty SD rats with similar behavior evaluation scores were randomly divided into 3 groups, control group (control), stimulation group (CUS), stimulation + fluoxetine group (CU). S + fluoxetine. The control group was normally fed and the remaining 2 groups were given chronic unpredictability stress in a total of 42 days, that system Depressive model.2. The drug intervention method intervenes with the use of fluoxetine To mimic the route of administration of the patient and administer it by gavage. Same volume of saline 3. The method of behavior evaluation adopts the change of body mass and the level of the body mass. Field test, sucrose water 4. The expression of the MKP-1 protein in the hippocampus was studied by means of the immunohistochemical method in the laboratory. chromatin immunoprecipitation a statistical method for the understanding of histone ethylation status by means of the (CHIP) method The data of the experiment was analyzed by the analysis of variance, and the data was analyzed by SPSS 13.0. Lemma. One-factor analysis of variance (one- wa y ANOVA) Results 1. The body mass, the horizontal movement distance and the water consumption of sucrose in each group were measured before the behavior evaluation. The proportion difference was not statistically significant (P = 0.699, P = 0.950, P = 0.996). After 21 days of chronic stress, the body mass, the horizontal movement distance, the sucrose water consumption ratio stimulation group (P = 0.003, P = 0.013, P = 0.009), stimulation + Flui The control group (P = 0.000, P = 0.022, P = 0.008) was significantly lower than that in the control group (P = 0.000, P = 0.022, P = 0.008). After 21 days of drug intervention, the mass of the stimulation group, the distance between the horizontal movement and the consumption of sucrose water were significantly lower than that of the control group (P = 0.000, P = 0.001, P = 0.000), and the level of the stimulation + fluorositin group was higher than that in the control group (P = 0.000, P = 0.001, P = 0.000). The percentage of sucrose water consumption was significantly higher than that in the stimulation group (P = 0.000, P = 0.000); the difference between the stimulation and the fluoxetine group and the control group was not statistically significant (P = 0.663, P = 0.087); the body mass stimulation group and the stimulation + Fluoxetine group was lower than that in the control group, and the difference was calculated (P = 0). (000, P = 0.000).2. The expression of MKP-1 in the hippocampus of the model rats and the expression of MKP-1 in the hippocampal CA1, CA3, and DG regions of the stimulated group of fluoxetine The difference was significant (P = 0.000, P = 0.000, P = 0.000). The difference was significant (P = 0.002, P = 0.009, P = 0). 000). There was no significant difference in the expression of MKP-1 in the hippocampal CA2 region of each group (P = 0). (828).3. The model rat hippocampal MKP-1 promoter region histone H3 B and the effect of fluoxetine in the hippocampus MK The level of histone H3 in the P-1 promoter region was significantly higher than that in the control group, and the difference was of statistical significance ( P = 0.004). There was no significant difference in the stimulation group and the stimulation group, and the difference was not statistically significant. to learn from one's The difference was statistically significant (P = 0.323) in the control group (P = 0.323). Conclusion 1. Chronic unpredictability stress The expression of MKP-1 in the hippocampus of the rat hippocampus increased with the level of histone H3 in the promoter region, and may be involved in the pathogenesis of depression.
【學(xué)位授予單位】：新鄉(xiāng)醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2013
【分類號(hào)】：R749.4
[Abstract]:background Depressive disorder is the main clinical characteristic of depression, which has the obvious chronic tendency, which seriously affects the physical and mental health of the patient, and causes the heavy disease to be negative The understanding of molecular biological mechanisms in the disorder of depression can help to improve the methods of treatment and to improve the pre-treatment In recent years, in recent years, in the relevant research, the signal system in the cell is gradually being paid attention to, and more and more research has found that the signal pathway in the cells, such as neuron proliferation, differentiation, maturation, survival, protrusion growth, and the like, is closely related to the depressive disorder. The MAPK signal system is located in the cell, can conduct various extracellular signals to the cell, cause the change of the expression of the gene, and the activity of the system in the central nervous system is closely related to the depression The results suggest that the overexpression of MKP-1 in the brain may be associated with the occurrence of depression as one of the negative regulation factors of the MAPK system. On the other hand, as one of the epigenetic modification mechanisms, the histone H3 ethylation of the promoter region can cause the increase of gene expression, and it is presumed that the histone H3 ethylation modification of the MKP-1 promoter region may also be involved in the development of depression. To study the relationship between the expression of MKP-1 and the histone H3 of its promoter region in the pathogenesis of depression. Bit. Objective: To study the expression of MKP-1 in hippocampus and the depression pattern of histone in the model of depression. 2. To study the effect of fluoxetine on the expression of MKP-1 in hippocampus and its promoter region histone B systematize A state-to-state relationship. Method 1. Experimental animals Thirty SD rats with similar behavior evaluation scores were randomly divided into 3 groups, control group (control), stimulation group (CUS), stimulation + fluoxetine group (CU). S + fluoxetine. The control group was normally fed and the remaining 2 groups were given chronic unpredictability stress in a total of 42 days, that system Depressive model.2. The drug intervention method intervenes with the use of fluoxetine To mimic the route of administration of the patient and administer it by gavage. Same volume of saline 3. The method of behavior evaluation adopts the change of body mass and the level of the body mass. Field test, sucrose water 4. The expression of the MKP-1 protein in the hippocampus was studied by means of the immunohistochemical method in the laboratory. chromatin immunoprecipitation a statistical method for the understanding of histone ethylation status by means of the (CHIP) method The data of the experiment was analyzed by the analysis of variance, and the data was analyzed by SPSS 13.0. Lemma. One-factor analysis of variance (one- wa y ANOVA) Results 1. The body mass, the horizontal movement distance and the water consumption of sucrose in each group were measured before the behavior evaluation. The proportion difference was not statistically significant (P = 0.699, P = 0.950, P = 0.996). After 21 days of chronic stress, the body mass, the horizontal movement distance, the sucrose water consumption ratio stimulation group (P = 0.003, P = 0.013, P = 0.009), stimulation + Flui The control group (P = 0.000, P = 0.022, P = 0.008) was significantly lower than that in the control group (P = 0.000, P = 0.022, P = 0.008). After 21 days of drug intervention, the mass of the stimulation group, the distance between the horizontal movement and the consumption of sucrose water were significantly lower than that of the control group (P = 0.000, P = 0.001, P = 0.000), and the level of the stimulation + fluorositin group was higher than that in the control group (P = 0.000, P = 0.001, P = 0.000). The percentage of sucrose water consumption was significantly higher than that in the stimulation group (P = 0.000, P = 0.000); the difference between the stimulation and the fluoxetine group and the control group was not statistically significant (P = 0.663, P = 0.087); the body mass stimulation group and the stimulation + Fluoxetine group was lower than that in the control group, and the difference was calculated (P = 0). (000, P = 0.000).2. The expression of MKP-1 in the hippocampus of the model rats and the expression of MKP-1 in the hippocampal CA1, CA3, and DG regions of the stimulated group of fluoxetine The difference was significant (P = 0.000, P = 0.000, P = 0.000). The difference was significant (P = 0.002, P = 0.009, P = 0). 000). There was no significant difference in the expression of MKP-1 in the hippocampal CA2 region of each group (P = 0). (828).3. The model rat hippocampal MKP-1 promoter region histone H3 B and the effect of fluoxetine in the hippocampus MK The level of histone H3 in the P-1 promoter region was significantly higher than that in the control group, and the difference was of statistical significance ( P = 0.004). There was no significant difference in the stimulation group and the stimulation group, and the difference was not statistically significant. to learn from one's The difference was statistically significant (P = 0.323) in the control group (P = 0.323). Conclusion 1. Chronic unpredictability stress The expression of MKP-1 in the hippocampus of the rat hippocampus increased with the level of histone H3 in the promoter region, and may be involved in the pathogenesis of depression.
【學(xué)位授予單位】：新鄉(xiāng)醫(yī)學(xué)院
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2013
【分類號(hào)】：R749.4
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