Majores Michael, Eils Jürgen, Wiestler Otmar D, Becker Albert J
Department of Neuropathology, University of Bonn Medical Center, Sigmund-Freud Street 25, D-53105 Bonn, Germany.
Epilepsy Res. 2004 Jul-Aug;60(2-3):173-8. doi: 10.1016/j.eplepsyres.2004.07.002.
The advent of gene chip technology and the era of functional genomics have initially been accompanied by huge anticipations to quickly unravel the molecular pathogenesis of multifactorial diseases. Expectations have, today, given way to some concerns about this non-hypothesis driven approach. However, the careful and controlled application of expression microarrays in concert with refined bioinformatic tools may provide novel insights in major disorders particularly of highly complex organs such as the central nervous system (CNS). Epilepsies are among the most frequent CNS disorders affecting approximately 1.5% of the population worldwide. In temporal lobe epilepsy (TLE), the seizure origin typically involves the hippocampal formation, a structure located in the mesial temporal lobe. Many TLE patients develop pharmacoresistance, i.e. seizures can no more be controlled by antiepileptic drugs. In order to achieve seizure control, surgical removal of the epileptogenic focus has been established as successful therapeutic strategy. Hippocampal biopsy tissue of pharmacoresistant TLE patients represents an excellent substrate to analyze molecular mechanisms related to structural and cellular reorganization in epilepsy. The complexity of alterations in TLE hippocampi suggests numerous genes and signaling cascades to be involved in the pathogenesis. By microarrays, genome wide expression profiles can be constituted from TLE tissues. However, hippocampi of pharmacoresistant TLE patients represent an advanced stage of the disease. Early stages of epilepsy development are not available for functional genome analysis in humans. Animal models of TLE appear particularly helpful to study molecular mechanisms of highly dynamic processes such as the development of hyperexcitability and pharmacoresistance. In this review, we summarize recent data of gene expression profiles in human and experimental TLE and discuss the relevance of novel tools for bioinformatic analysis and data mining.
基因芯片技术的出现以及功能基因组学时代的到来，最初伴随着人们极大的期望，即迅速揭示多因素疾病的分子发病机制。如今，这些期望已让位于对这种非假说驱动方法的一些担忧。然而，将表达微阵列与精细的生物信息学工具协同进行仔细且可控的应用，可能会为重大疾病，尤其是像中枢神经系统（CNS）这样高度复杂器官的疾病，提供新的见解。癫痫是最常见的中枢神经系统疾病之一，全球约1.5%的人口受其影响。在颞叶癫痫（TLE）中，癫痫发作起源通常涉及海马结构，该结构位于颞叶内侧。许多TLE患者会出现药物抵抗，即癫痫发作无法再通过抗癫痫药物控制。为了实现癫痫发作的控制，手术切除致痫灶已成为一种成功的治疗策略。药物抵抗性TLE患者的海马活检组织是分析癫痫中与结构和细胞重组相关分子机制的理想样本。TLE海马中改变的复杂性表明众多基因和信号级联参与了发病机制。通过微阵列，可以从TLE组织构建全基因组表达谱。然而，药物抵抗性TLE患者的海马代表了疾病的晚期阶段。癫痫发展的早期阶段无法用于人类功能基因组分析。TLE动物模型对于研究诸如兴奋性过高和药物抵抗性发展等高度动态过程的分子机制似乎特别有帮助。在这篇综述中，我们总结了人类和实验性TLE中基因表达谱的最新数据，并讨论了生物信息学分析和数据挖掘新工具的相关性。
