Comprehensive transcriptional profiling of prion infection in mouse models reveals networks of responsive genes.
Comprehensive transcriptional profiling of prion infection in mouse models reveals networks of responsive genes.
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DOI：
10.1186/1471-2164-9-114
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发表时间：
2008-03-03
期刊：
影响因子：
4.4
通讯作者：
Booth SA
中科院分区：
文献类型：
--
作者：
Sorensen G;Medina S;Parchaliuk D;Phillipson C;Robertson C;Booth SA
朊病毒感染会导致中枢神经系统的进行性神经变性，最终导致死亡。朊病毒疾病在大脑中的病理作用在形态学上是明确的，如胶质细胞形成、空泡形成和疾病特异性蛋白酶抗性朊病毒蛋白（PrPSc）的积累。然而，导致神经元死亡的潜在分子事件却没有得到很好的描述。在这项研究中，利用cDNA微阵列分析了感染三种小鼠适应痒病的两种不同菌株的小鼠大脑中基因表达的变化。收集和分析了大量数据，从中我们确定了349个朊病毒相关基因（PRGs）的核心组，这些基因在小鼠模型中一致显示表达改变。基因本体论分析将许多上调基因分配到与朊病毒疾病，星形细胞增生和胶质细胞增生的主要神经病理特征之一相关的功能组；蛋白质合成，炎症，细胞增殖和脂质代谢。利用一种计算工具，匠心途径分析（Ingenuity Pathway Analysis， IPA），我们能够从PRG列表中构建相互作用基因的网络。参与调节炎症反应的调节性细胞因子TGFB1被确定为许多PRGs的杰出相互作用伙伴。神经元中大部分基因表达下调；其中一些参与了包括突触功能、钙信号、长期增强和ERK/MAPK信号在内的调控途径。编码转录调控因子的两个下调基因EGR1和CREB1也被确定为基因相互作用网络的核心；这些因子通常被用作神经元活动的标记，它们的失调可能是神经元功能丧失的关键。这些数据提供了在多种痒病感染小鼠模型中一致差异表达的基因的全面列表。在这些基因之间建立相互作用的网络提供了一种理解神经退行性变期间大脑中复杂相互作用的方法。解决朊病毒发病机制的关键调控和信号事件将为新疗法的设计和生物标志物的阐明提供靶点。
Prion infection results in progressive neurodegeneration of the central nervous system invariably resulting in death. The pathological effects of prion diseases in the brain are morphologically well defined, such as gliosis, vacuolation, and the accumulation of disease-specific protease-resistant prion protein (PrPSc). However, the underlying molecular events that lead to the death of neurons are poorly characterised. In this study cDNA microarrays were used to profile gene expression changes in the brains of two different strains of mice infected with three strains of mouse-adapted scrapie. Extensive data was collected and analyzed, from which we identified a core group of 349 prion-related genes (PRGs) that consistently showed altered expression in mouse models. Gene ontology analysis assigned many of the up-regulated genes to functional groups associated with one of the primary neuropathological features of prion diseases, astrocytosis and gliosis; protein synthesis, inflammation, cell proliferation and lipid metabolism. Using a computational tool, Ingenuity Pathway Analysis (IPA), we were able to build networks of interacting genes from the PRG list. The regulatory cytokine TGFB1, involved in modulating the inflammatory response, was identified as the outstanding interaction partner for many of the PRGs. The majority of genes expressed in neurons were down-regulated; a number of these were involved in regulatory pathways including synapse function, calcium signalling, long-term potentiation and ERK/MAPK signalling. Two down-regulated genes coding for the transcription regulators, EGR1 and CREB1, were also identified as central to interacting networks of genes; these factors are often used as markers of neuronal activity and their deregulation could be key to loss of neuronal function. These data provides a comprehensive list of genes that are consistently differentially expressed in multiple scrapie infected mouse models. Building networks of interactions between these genes provides a means to understand the complex interplay in the brain during neurodegeneration. Resolving the key regulatory and signaling events that underlie prion pathogenesis will provide targets for the design of novel therapies and the elucidation of biomarkers.
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DOI：
10.1111/j.1749-6632.2002.tb04801.x
发表时间：
2002-01-01
期刊：
ALZHEIMER'S DISEASE: VASCULAR ETIOLOGY AND PATHOLOGY
影响因子：
--
作者：
Buckwalter, M;Pepper, JP;Wyss-Coray, T
通讯作者：
Wyss-Coray, T
影响因子：
6.1
作者：
Boche, Delphine;Cunningham, Colm;Perry, V. Hugh
通讯作者：
Perry, V. Hugh
DOI：
10.1097/00004647-200001000-00013
发表时间：
2000-01-01
影响因子：
6.3
作者：
Koponen, S;Goldsteins, G;Koistinaho, J
通讯作者：
Koistinaho, J
影响因子：
5.3
作者：
Buckwalter, Marion S.;Coleman, Bronwen S.;Wyss-Coray, Tony
通讯作者：
Wyss-Coray, Tony
影响因子：
5
作者：
Cunningham, C;Boche, D;Perry, VH
通讯作者：
Perry, VH