Probing the Role of Polycomb in the Epigenetics of Epilepsy

 描述(申请人提供)：癫痫是仅次于中风和阿尔茨海默病的第三大最常见的神经疾病，发病率为每26人中有1人。癫痫发生是指癫痫发作阈值的逐渐降低，最终导致无缘无故的自发性癫痫发作，其频率、严重程度和持续时间可能会增加。虽然有许多抗癫痫药物可用，但没有任何抗癫痫药物可以减缓疾病的进展。与癫痫发生相关的基因表达的长期变化表明，一个或多个转录调控大师可能正在协调大脑的变化。为了揭示这些遗传机制，我们求助于癫痫微阵列联盟生成的全基因组表达数据集。这些数据集包括在癫痫持续状态(S.E)后不同时间点检测的小鼠齿状回颗粒细胞的mRNA表达谱。由于这些数据集来自3种不同的惊厥刺激诱导的大脑，每个都在2个不同的实验室，在不同的时间点，这给了我们机会来辨别基因网络中的模型无关和实验室无关的变化。我们使用我们开发的一种创新的生物信息学工具来揭示驱动癫痫联合体数据库中观察到的基因变化的转录因子和核蛋白。我们发现，一种名为Polycomb的主要表观遗传复合体驱动了跨越实验室、模型和时间的大部分基因变化。这是令人兴奋的，因为Polycomb是众所周知的基因表达终身变化的驱动力，其工作原理是在整个门的身体计划建立期间，通过表观遗传沉默基因。我们的初步数据显示，由Polycomb独特催化的表观遗传标记在癫痫发作后24小时内在海马区诱导，并在癫痫发作后至少5天保持不变。在这项建议中，我们将检验Polycomb输出的改变是癫痫发生的主要修饰物的假设：我们将确定Polycomb活动的增加是病理性的还是保护性的。我们将测试Polycomb的药理调节是否可以改变癫痫发生的过程，从而潜在地识别一类新的药物。小分子聚梳抑制剂，如那些正在进行淋巴瘤临床试验的药物，将被测试其在延缓癫痫发生方面的有效性。我们预计这些研究将使Polycomb成为一种 与癫痫发生相关的长期变化的主要策划者。如果是这样的话，调节Polycomb功能的方法可能会使全球6500万癫痫患者受益。

 DESCRIPTION (provided by applicant): Epilepsy is the third most prevalent neurological disorder after stroke and Alzheimer's disease with an incidence of 1 in 26 individuals. Epileptogenesis refers to the progressive decrease in seizure threshold that ultimately results in unprovoked, spontaneous seizures that may increase in frequency, severity and duration. Though there are a number of anti-convulsant drugs available, there are no anti-epileptogenic drugs that mitigate the progression of the disease. Long-term changes in gene expression that are associated with epileptogenesis imply that one or more master regulators of transcription may be coordinating the brain alterations. In order to uncover these genetic mechanisms, we turned to the genome-wide expression datasets generated by the Epilepsy Microarray Consortium. The datasets consist of mRNA expression profiles of mouse dentate granule cells assayed at various time points after Status Epilepticus (S.E). Because these datasets are derived from brains induced by 3 different convulsant stimuli, each in 2 different labs, and at various time-points, this gives us the opportunity to discern model-independent and lab-independent alterations in gene networks. We used an innovative and novel bioinformatics tool developed by us to reveal the transcription factors and nuclear proteins that drive gene changes observed in the Epilepsy Consortium dataset. We found that a master epigenetic complex called Polycomb drives the majority of gene changes across labs, models and time. This is exciting because Polycomb is a well-known driver of life-long changes in gene expression that works by epigenetically silencing genes during body plan establishment across the phyla. Our preliminary data shows that the epigenetic mark uniquely catalyzed by Polycomb is induced in the hippocampus within 24hrs after seizures and remains at least 5 days after the seizure. In this proposal we will test the hypothesis that an alteration in Polycomb output is a principle modifier of epileptogenesis: we will determine whether the increase in Polycomb activity is pathological or protective. We will test whether pharmacological modulation of Polycomb can alter the process of epileptogenesis and thus potentially identify a novel class of drugs. Small molecule inhibitors of Polycomb such as those in clinical trials for lymphoma will be tested for their efficacy in stalling epileptogenesis. We anticipate that these studies will establish Polycomb as a major orchestrator of the long-term changes associated with epileptogenesis. If so, approaches that modulate Polycomb function may be of benefit to the 65 million people world- wide that live with epilepsy.