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双相情感障碍及共病酒精中毒应激反应性遗传动物模型中的表型组学、整合功能基因组学和生物标志物研究。

Phenomic, convergent functional genomic, and biomarker studies in a stress-reactive genetic animal model of bipolar disorder and co-morbid alcoholism.

作者信息

Le-Niculescu H, McFarland M J, Ogden C A, Balaraman Y, Patel S, Tan J, Rodd Z A, Paulus M, Geyer M A, Edenberg H J, Glatt S J, Faraone S V, Nurnberger J I, Kuczenski R, Tsuang M T, Niculescu A B

机构信息

Laboratory of Neurophenomics, Indiana University School of Medicine, Indianapolis, Indiana.

出版信息

Am J Med Genet B Neuropsychiatr Genet. 2008 Mar 5;147B(2):134-66. doi: 10.1002/ajmg.b.30707.

Abstract

We had previously identified the clock gene D-box binding protein (Dbp) as a potential candidate gene for bipolar disorder and for alcoholism, using a Convergent Functional Genomics (CFG) approach. Here we report that mice with a homozygous deletion of DBP have lower locomotor activity, blunted responses to stimulants, and gain less weight over time. In response to a chronic stress paradigm, these mice exhibit a diametric switch in these phenotypes. DBP knockout mice are also activated by sleep deprivation, similar to bipolar patients, and that activation is prevented by treatment with the mood stabilizer drug valproate. Moreover, these mice show increased alcohol intake following exposure to stress. Microarray studies of brain and blood reveal a pattern of gene expression changes that may explain the observed phenotypes. CFG analysis of the gene expression changes identified a series of novel candidate genes and blood biomarkers for bipolar disorder, alcoholism, and stress reactivity.

摘要

我们之前采用整合功能基因组学(CFG)方法,将生物钟基因D-盒结合蛋白(Dbp)鉴定为双相情感障碍和酒精中毒的潜在候选基因。在此我们报告,Dbp基因纯合缺失的小鼠运动活性较低,对兴奋剂的反应迟钝,且随着时间推移体重增加较少。在慢性应激范式下,这些小鼠在这些表型上表现出截然相反的变化。与双相情感障碍患者相似,Dbp基因敲除小鼠也会因睡眠剥夺而被激活,而这种激活可通过使用情绪稳定剂丙戊酸盐进行治疗来预防。此外,这些小鼠在受到应激后酒精摄入量增加。对大脑和血液的微阵列研究揭示了一种基因表达变化模式,这可能解释所观察到的表型。对基因表达变化的CFG分析确定了一系列用于双相情感障碍、酒精中毒和应激反应性的新型候选基因和血液生物标志物。

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