抑郁症相关蛋白树突细胞核蛋白-1对促肾上腺皮质激素释放激素调节的研究
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摘要
抑郁是一个与悲痛和哀伤紧密相关的正常情感,但即使消除导致抑郁的外部环境因素,情绪也不会因此缓和。抑郁情绪的堆积导致抑郁症,而导致抑郁症的外部原因并不确定,抑郁症常见的严重症状一般是没有特定的直接性外源因素。抑郁症的诊断是根据情绪的不同变化,具有悲伤,易怒的特征并伴随有至少一些心理或生理性疾病的改变,例如睡眠、食欲、性欲等紊乱,便秘,哭泣,失去工作或与朋友相处时的快乐,有自杀想法,语言、行动迟缓等。这些改变至少要持续两周并且相当程度的影响着与工作、家庭间的关系。抑郁症是一个由不同因素形成的精神障碍,具有高度变化的过程,对于抗抑郁药物治疗的反应也不一致,至今抑郁症的发病机制尚不明确。目前已知的抑郁症发病机理可能包括：1)遗传因素；2)单胺类缺乏假说；3)应激,下丘脑-垂体-肾上腺皮质轴(Hypothalamic-Pituitary-Adrenal axis, HPA-axis)和生长因子。HPA轴在抑郁症的过度激活可能由于遗传因素或是早期发育／整个生命活动中受到的后抑刺激。在下丘脑内,至少有五个相互作用的肽能系统参与了抑郁症发生所表现出的症状。
其中,促肾上腺皮质激素释放激素(CRH)是在下丘脑肽能中控制HPA轴的关键,在机体内对应激反应起到十分重要的作用。CRH第一次是由Vale提出,它是一个由41个氨基酸构成的下丘脑神经肽,可以分泌促肾上腺皮质激素和p内啡肽(Vale et al.,1981)。CRH在各个物种中具有相对的保守性,在人(Shibahara, Morimoto et al.1983)、大鼠(Rivier, Spiess et al.1983)、绵羊(Vale, Spiess et al. 1981)、马(Livesey, Carne et al.1991)以及牛(Esch, Ling et al.1984)中分别都有发现。其中人、大鼠和马的CRH具有相同的结构特征。当机体受到外界应激刺激后,CRH在下丘脑室旁核(PVN)神经肽的合成增加,通过神经纤维传递,经正中隆起(median elemence, ME),通过垂体门脉系统,运送到腺垂体(adrenohypophysis),刺激促肾上腺皮质激素(adrenocorticotropin, ACTH)从腺垂体细胞释放(Vale et al.,1981); ACTH释放到体循环内,(在人体内)导致肾上腺皮质分泌糖皮质激素；最后,糖皮质激素又负反馈调节ACTH及CRH (Erkut, Pool et al.1998)。
最近的研究表明树突状细胞核蛋白-1(DCNP1)是抑郁症新发现的可能候选基因产物。在DCNP1氨基酸序列5'端,第117位密码子T等位基因编码一个提前终止的截短型DCNP1(DCNP11-116),而A等位基因则编码全长的DCNP1。由于之前有报道DCNP1与抑郁症相关(Willis-Owen, Shifman et al.2006),因此我们想在实验中研究是否两种类型的DCNP1都可能相互作用于CRH。由于CRH在应激反应以及抑郁症发病中的重要关系,因此也可以证明DCNP1在抑郁症中可能发挥的作用。我们通过激光显微切割技术和qPCR实验发现DCNP1的mRNA水平在抑郁症病人中相对于正常对照组有明显的增加；另外,我们还利用荧光免疫组织化学和激光共聚焦技术发现DCNP1在下丘脑室旁核与CRH有共定位现象。最后,在人的胚胎肾细胞实验中,采用染色体免疫沉淀技术发现全长的DCNP1可以与CRH相互作用,并且通过荧光素酶活性报告基因实验中发现全长DCNP1可以在细胞中激活CRH启动子；而截短型DCNP1 (DCNP11-116)并没有发现对CRH有明显的作用。因此我们提出全长的DCNP1可能在抑郁症发病机理中通过增强下丘脑室旁核中CRH的表达在抑郁症病人中也发挥了作用。
Depression is related to the normal emotions of sadness and bereavement, but it does not remit when the external cause of these emotions dissipates, and it is disproportionate to their cause. Classic severe states of depression often have no external precipitating cause. The diagnosis of major depressive disorder requires a distinct change of mood, characterized by sadness or irritability and accompanied by at least several psychophysiological changes, such as disturbances in sleep, appetite, or sexual desire; constipation; loss of the ability to experience pleasure in work or with friends; crying; suicidal thoughts; and slowing of speech and action. These changes must last a minimum of two weeks and interfere considerably with work and family relations. Depression is a heterogeneous disorder with a highly variable course, an inconsistent response to treatment, and no established mechanism. The possible mechanisms of depression include genetics, the monoamine-deficiency hypothesis, the hypothalamic-pituitary-adrenal axis, growth factors and other possible mechanisms. The hypothalamic-pituitary-adrenal (HPA) axis is hyperactive in depression, due to genetic factors or aversive stimuli that may occur during early development or adult life. At least five interacting hypothalamic peptidergic systems are involved in the symptoms of major depression.
Corticotropin releasing hormone (CRH) is the key hypothalamic peptide controlling the HPA-axis. It plays a central role in the response of the organism to stress. As a 41-residue hypothalamic peptide, CRH was first described by Vale (Vale et al.1981). It could stimulate secretion of corticotropin and beta-endorphin (Vale et al.,1981). CRH is charactered with relative conservation. It was found in human (Shibahara, Morimoto et al.,1983), rat (Rivier, Spiess et al.1983), sheep (Vale, Spiess et al.1981), horse (Livesey, Carne et al.1991) and cow (Esch, Ling et al.1984). There is the same structure feature between human, rat and horse. After exposure to stress, the synthesis of CRH is increased in peptidergic neurons in the paraventricular nucleus (PVN) of the hypothalamus, leading to the release of the peptide from the median eminence. CRH is transported through the portal vascular system to the pituitary, and stimulates the secretion of adrenocorticotropin (ACTH) from anterior pituitary cells (Vale et al.,1981). ACTH is secreted into the systemic circulation, leading (in humans) to the secretion of cortisol from the adrenal cortex. At the last, the cortisol also negative feedback regulated ACTH and CRH again (Erkut, Pool et al. 1998).
The recently discovered dendritic cell nuclear protein-1 (DCNPl) is the product of a novel candidate gene for major depression. The A allele encodes full-length DCNP1, while the T allele encodes a premature termination of translation at codon number 117 on chromosome 5 (Willis-Owen, Shifman et al.2006). In the present study we investigate whether the two forms of DCNP1 might act on CRH, which plays a crucial role in the stress response and in the pathogenesis of depression. The mRNA expression of DCNP1 appeared to be increased in the laser micro-dissected PVN of depressed patients as compared to control subjects. In addition, DCNP1 was found to be co-localized with CRH in PVN neurons performed with immunofluorescence and confocal laser scanning microscopy. Moreover, with chromatin immunoprecipitation, immunoblot analysis and dual-luciferase reporter gene assay, full-length DCNP1 bound to and transactivated the promoter of CRH in human embryonic kidney 293 cells. We propose that full-length DCNP1 may play a role in the pathogenesis of depressive disorders by enhancing CRH expression in the hypothalamic paraventricular nucleus.
其中,促肾上腺皮质激素释放激素(CRH)是在下丘脑肽能中控制HPA轴的关键,在机体内对应激反应起到十分重要的作用。CRH第一次是由Vale提出,它是一个由41个氨基酸构成的下丘脑神经肽,可以分泌促肾上腺皮质激素和p内啡肽(Vale et al.,1981)。CRH在各个物种中具有相对的保守性,在人(Shibahara, Morimoto et al.1983)、大鼠(Rivier, Spiess et al.1983)、绵羊(Vale, Spiess et al. 1981)、马(Livesey, Carne et al.1991)以及牛(Esch, Ling et al.1984)中分别都有发现。其中人、大鼠和马的CRH具有相同的结构特征。当机体受到外界应激刺激后,CRH在下丘脑室旁核(PVN)神经肽的合成增加,通过神经纤维传递,经正中隆起(median elemence, ME),通过垂体门脉系统,运送到腺垂体(adrenohypophysis),刺激促肾上腺皮质激素(adrenocorticotropin, ACTH)从腺垂体细胞释放(Vale et al.,1981); ACTH释放到体循环内,(在人体内)导致肾上腺皮质分泌糖皮质激素；最后,糖皮质激素又负反馈调节ACTH及CRH (Erkut, Pool et al.1998)。
最近的研究表明树突状细胞核蛋白-1(DCNP1)是抑郁症新发现的可能候选基因产物。在DCNP1氨基酸序列5'端,第117位密码子T等位基因编码一个提前终止的截短型DCNP1(DCNP11-116),而A等位基因则编码全长的DCNP1。由于之前有报道DCNP1与抑郁症相关(Willis-Owen, Shifman et al.2006),因此我们想在实验中研究是否两种类型的DCNP1都可能相互作用于CRH。由于CRH在应激反应以及抑郁症发病中的重要关系,因此也可以证明DCNP1在抑郁症中可能发挥的作用。我们通过激光显微切割技术和qPCR实验发现DCNP1的mRNA水平在抑郁症病人中相对于正常对照组有明显的增加；另外,我们还利用荧光免疫组织化学和激光共聚焦技术发现DCNP1在下丘脑室旁核与CRH有共定位现象。最后,在人的胚胎肾细胞实验中,采用染色体免疫沉淀技术发现全长的DCNP1可以与CRH相互作用,并且通过荧光素酶活性报告基因实验中发现全长DCNP1可以在细胞中激活CRH启动子；而截短型DCNP1 (DCNP11-116)并没有发现对CRH有明显的作用。因此我们提出全长的DCNP1可能在抑郁症发病机理中通过增强下丘脑室旁核中CRH的表达在抑郁症病人中也发挥了作用。
Depression is related to the normal emotions of sadness and bereavement, but it does not remit when the external cause of these emotions dissipates, and it is disproportionate to their cause. Classic severe states of depression often have no external precipitating cause. The diagnosis of major depressive disorder requires a distinct change of mood, characterized by sadness or irritability and accompanied by at least several psychophysiological changes, such as disturbances in sleep, appetite, or sexual desire; constipation; loss of the ability to experience pleasure in work or with friends; crying; suicidal thoughts; and slowing of speech and action. These changes must last a minimum of two weeks and interfere considerably with work and family relations. Depression is a heterogeneous disorder with a highly variable course, an inconsistent response to treatment, and no established mechanism. The possible mechanisms of depression include genetics, the monoamine-deficiency hypothesis, the hypothalamic-pituitary-adrenal axis, growth factors and other possible mechanisms. The hypothalamic-pituitary-adrenal (HPA) axis is hyperactive in depression, due to genetic factors or aversive stimuli that may occur during early development or adult life. At least five interacting hypothalamic peptidergic systems are involved in the symptoms of major depression.
Corticotropin releasing hormone (CRH) is the key hypothalamic peptide controlling the HPA-axis. It plays a central role in the response of the organism to stress. As a 41-residue hypothalamic peptide, CRH was first described by Vale (Vale et al.1981). It could stimulate secretion of corticotropin and beta-endorphin (Vale et al.,1981). CRH is charactered with relative conservation. It was found in human (Shibahara, Morimoto et al.,1983), rat (Rivier, Spiess et al.1983), sheep (Vale, Spiess et al.1981), horse (Livesey, Carne et al.1991) and cow (Esch, Ling et al.1984). There is the same structure feature between human, rat and horse. After exposure to stress, the synthesis of CRH is increased in peptidergic neurons in the paraventricular nucleus (PVN) of the hypothalamus, leading to the release of the peptide from the median eminence. CRH is transported through the portal vascular system to the pituitary, and stimulates the secretion of adrenocorticotropin (ACTH) from anterior pituitary cells (Vale et al.,1981). ACTH is secreted into the systemic circulation, leading (in humans) to the secretion of cortisol from the adrenal cortex. At the last, the cortisol also negative feedback regulated ACTH and CRH again (Erkut, Pool et al. 1998).
The recently discovered dendritic cell nuclear protein-1 (DCNPl) is the product of a novel candidate gene for major depression. The A allele encodes full-length DCNP1, while the T allele encodes a premature termination of translation at codon number 117 on chromosome 5 (Willis-Owen, Shifman et al.2006). In the present study we investigate whether the two forms of DCNP1 might act on CRH, which plays a crucial role in the stress response and in the pathogenesis of depression. The mRNA expression of DCNP1 appeared to be increased in the laser micro-dissected PVN of depressed patients as compared to control subjects. In addition, DCNP1 was found to be co-localized with CRH in PVN neurons performed with immunofluorescence and confocal laser scanning microscopy. Moreover, with chromatin immunoprecipitation, immunoblot analysis and dual-luciferase reporter gene assay, full-length DCNP1 bound to and transactivated the promoter of CRH in human embryonic kidney 293 cells. We propose that full-length DCNP1 may play a role in the pathogenesis of depressive disorders by enhancing CRH expression in the hypothalamic paraventricular nucleus.
引文
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