Ahi1调控GR信号通路在抑郁行为中的机制研究

发布时间：2018-05-06 17:28

本文选题：Abelson + helper　；参考：《苏州大学》2016年博士论文

【摘要】：抑郁症是常见的应激相关精神疾病,机体慢性长期或者过度的暴露于应激,下丘脑-垂体-肾上腺(HPA)轴被持续激活,机体会释放过量的糖皮质激素,研究认为HPA轴功能调节异常是近年来重症抑郁症发病机制研究中最可靠的发现。此外,临床研究中也发现在长期接受糖皮质激素治疗的患者中抑郁症高发。糖皮质激素受体(GR)作为HPA轴的末端效应器,参与HPA轴负反馈调节,介导机体对应激的反应,在抑郁症的发病和治疗中发挥重要作用。因此,探讨应激/糖皮质激素导致的抑郁症的神经生物学机制对医学研究来说具有重要意义。Abelson helper integration site 1(Ahi1)基因是遗传性神经发育迟滞疾病Joubert综合症的致病基因,我们过去的研究工作和一些相关的研究证实Ahi1基因也是抑郁症相关的易感基因。在本文中,我们证实了Ahi1通过调控GR信号通路,参与了抑郁症的发病与抗抑郁治疗过程。首先,我们利用环境应激和糖皮质激素诱导小鼠抑郁样行为改变,在抑郁模型小鼠的大脑不同脑区观察到Ahi1蛋白水平显著降低,该现象在糖皮质激素处理的体外细胞模型中得到验证。其次,Ahi1蛋白在脑神经元胞浆中表达与GR共定位,相互结合,过多的糖皮质激素增加配体依赖性GR核转移,降低了胞浆中GR/Ahi1复合物的稳定性,加速Ahi1蛋白通过泛素化途径降解。Ahi1的缺失进一步促进GR核转移,降低细胞浆GR的水平,从而损害GR对HPA轴的负反馈调节功能。此外,我们还证实了以前的发现,Ahi1的缺失可导致了酪氨酸激酶受体B/脑源性神经营养因子(TrkB/BDNF)信号通路的衰减而诱导抑郁样表型。Ahi1基因敲除小鼠表达低水平的GR,存在抑郁样行为,还表现出对环境应激,糖皮质激素和抗抑郁药物治疗作用的反应抵抗。过表达Ahi1可以恢复GR的蛋白水平,抑制其过度核转移,提示Ahi1的抗抑郁作用。最后,本文通过临床研究,在经过有效的抗抑郁药物治疗的患者外周血中检测到了增高的Ahi1表达水平。这些结果表明,Ahi1可能是新的抗抑郁药物研发靶点,并有潜力成为诊断和治疗抑郁症的有效的生物学标志物。
[Abstract]:Depression is a common stress-related mental disease, chronic or excessive exposure to stress, the hypothalamus-pituitary-adrenal gland (HPA) axis is continuously activated, the body will release excessive glucocorticoid, It is believed that abnormal HPA axis regulation is the most reliable finding in the pathogenesis of severe depression in recent years. In addition, clinical studies also found a high incidence of depression in patients with long-term glucocorticoid therapy. Glucocorticoid receptor (GRG), as the terminal effector of HPA axis, participates in the negative feedback regulation of HPA axis, mediates the body's response to stress, and plays an important role in the pathogenesis and treatment of depression. Therefore, to explore the neurobiological mechanism of stress / glucocorticoid induced depression is of great significance for medical research. Abelson helper integration site 1 (Ahi1) gene is the pathogenic gene of Joubert syndrome, a hereditary neurodevelopmental retardation. Our previous work and some related studies have confirmed that the Ahi1 gene is also a susceptible gene associated with depression. In this paper, we demonstrated that Ahi1 is involved in the pathogenesis and antidepressant treatment of depression by regulating the gr signaling pathway. First of all, we used environmental stress and glucocorticoid to induce depressive behavior in mice. We observed a significant decrease in Ahi1 protein levels in different brain regions of depression model mice. This phenomenon was verified in a glucocorticoid-treated cell model in vitro. Secondly, the expression of Ahi1 protein in the cytoplasm of brain neurons was co-located and combined with gr. Excessive glucocorticoids increased ligand-dependent gr nuclear metastasis and decreased the stability of GR/Ahi1 complex in the cytoplasm. Accelerating the degradation of .Ahi1 by the ubiquitin pathway further promotes the nuclear transfer of gr and reduces the level of cytoplasm gr, which impairs the negative feedback regulation of gr on HPA axis. In addition, we also confirmed that the absence of Ahi1 previously found may lead to the attenuation of the signal pathway of tyrosine kinase receptor B / brain-derived neurotrophic factor TrkB / BDNF.Ahi1 gene knockout mice have low expression of GRand and depressive behavior. They also showed resistance to environmental stress, glucocorticoid and antidepressants. Overexpression of Ahi1 can restore the protein level of gr and inhibit its excessive nuclear metastasis, suggesting the antidepressant effect of Ahi1. Finally, the increased expression of Ahi1 was detected in peripheral blood of patients treated with effective antidepressants. These results suggest that Ahi1 may be a new target for the development of antidepressants and has the potential to be an effective biomarker for the diagnosis and treatment of depression.
【学位授予单位】：苏州大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R749.4

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