Gene set enrichment analyses revealed several affected pathways in Niemann-Pick disease type C fibroblasts
Gene set enrichment analyses revealed several affected pathways in Niemann-Pick disease type C fibroblasts
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DOI：
10.1089/dna.2006.0570
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发表时间：
2007-09-01
影响因子：
3.1
通讯作者：
Laaksonen, Reijo
中科院分区：
文献类型：
--
作者：
De Windt, Aloys;Rai, Myriam;Laaksonen, Reijo
尼曼匹克C型（NPC）病的特征是脂质的内体和溶酶体积聚，小管囊泡运输受损和导致过早死亡的神经变性。目前的治疗选择主要限于对症治疗。因此，需要新的有效的药物靶标，因此我们对NPC和健康成纤维细胞进行了基因集富集分析（GSEA），以鉴定NPC中受全球影响的途径，这些途径可以作为以后药物发现计划的靶标。通过分析细胞内胆固醇、其前体和代谢物的浓度以及细胞内植物甾醇水平来表征细胞系。用Sentrix（R）Human-8 Expression BeadChips进行基因表达分析，分析23，000个转录物。使用GSEA方法进行表达数据的途径分析。在GSEA分析中，27个上调和33个下调的途径受到全球影响。这些途径包括例如线粒体途径、半胱天冬酶级联以及前列腺素和白三烯代谢。根据目前的结果和早期发表的数据，抗炎和抗凋亡治疗可能对NPC有益。
Niemann-pick type C (NPC) disease is characterized by endosomal and lysosomal accumulation of lipids, impaired tubulovesicular trafficking, and neurodegeneration leading to premature death. Current treatment options are limited to mainly symptomatic treatments. Thus, new and efficient drug targets are needed, and therefore we performed a Gene Set Enrichment Analysis (GSEA) on NPC and healthy fibroblasts to identify globally affected pathways in NPC that could serve as targets for later drug discovery programs. Cell lines were characterized by analyzing cellular concentrations of cholesterol, its precursors and metabolites, as well as cellular plant sterol levels. Gene expression analyses were performed with Sentrix (R) Human-8 Expression BeadChips, analyzing 23,000 transcripts. Pathway analysis of the expression data was performed using the GSEA method. Twenty-seven upregulated and 33 downregulated pathways emerged as globally affected in the GSEA analysis. These pathways included, for example, mitochondrial pathway, caspase cascade, as well as prostaglandin and leukotriene metabolism. Based on the present results and earlier published data, anti-inflammatory and antiapoptotic treatment could be beneficial in NPC.