Proteomic Profiles in Human Temporal Lobe Epilepsy

描述（由申请人提供）：癫痫影响美国约250万人，全球约4000万人。其中40%是颞叶癫痫（TLE）患者。在大约45%的TLE患者中，癫痫发作不能通过现有药物得到很好的控制。手术可以帮助这些患者中的一部分，但仍然是一种昂贵的手术，有发病的风险。TLE的分子机制尚未完全阐明，但如果进一步了解，可能为该病的治疗和/或治愈提供新的途径。基因（基因组学）和蛋白质（蛋白质组学）表达的高通量筛选方法的最新发展有望在揭示这些分子机制方面取得更快速的进展。在最近收到的R21的支持下，我们已经开始识别与TLE患者癫痫性脑灶病理生理相关的各种基因和途径。然而，基因表达分析本身并不能提供由已鉴定基因编码的实际蛋白质的可靠信息。由于编辑和剪接的不同，单个基因可以编码多种不同的蛋白质，它们的产物可能出现翻译后修饰。在这个建议中，我们建议分析海马癫痫病灶的蛋白质组，以补充正在进行的基因组研究。在这些研究中，我们将使用2-DIGE分析来确定具有海马硬化（MTLE）特征的内侧颞叶癫痫的蛋白质谱。在矛盾性颞叶癫痫（PTLE）患者中，只有二分之一的患者在手术后经历无癫痫发作状态，蛋白质组学特征将与手术结果进行比较，以阐明不良反应者的蛋白质组学，作为开发该组术前分子诊断的一种手段。这些研究对于识别TLE特有的分子至关重要，这些分子将成为未来研究的候选分子，以探索它们在癫痫发作机制中的作用。

DESCRIPTION (provided by applicant): Epilepsy affects about 2.5 million people in the USA and 40 million worldwide. Of this population 40% are patients with temporal lobe Epilepsy (TLE). In approximately 45% of those with TLE, seizures cannot be well controlled by available medications. Surgery helps a proportion of these patients, but remains a costly procedure with a risk of morbidity. The molecular mechanisms of TLE are not yet fully elucidated, but if better known could provide new avenues for the treatment and/or cure of this disease. Recent developments in methods for high throughput screening of gene (genomics) and protein (proteomics) expression hold promise of more rapid progress in unravelling these molecular mechanisms. We have begun to identify various genes and pathways associated with the pathophysiology of epileptic brain foci from TLE patients supported by a recently received R21. However, gene expression analyses do not by themselves provide reliable information on the actual proteins encoded by identified genes. A single gene can encode many different protein species due to differences in editing and splicing, and their products may show post- translational modification. In this proposal we propose to analyze the proteome in hippocampal seizure foci, to complement genomic studies in progress. In these studies we will use 2-DIGE analyses to identify the protein profile that characterizes mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE). In patients with paradoxical temporal lobe epilepsy (PTLE), where only one in two patients experience seizure free status after surgery, proteomic profiles will be compared with surgical outcome, to elucidate the proteome of the poor responders, as a means to developing a presurgical molecular diagnosis of this group. These studies are essential to identify molecules unique to TLE, which will be the candidates for study in future research that explores their role(s) in seizure mechanisms.