Transcriptional Repression Therapeutic Target/Epilepsy

描述（由申请人提供）： 癫痫持续状态和其他对中枢神经系统的损伤性刺激，如创伤性脑损伤，触发海马神经元的各种反应。我们最近描述了一个急性转录抑制的广泛阵列的神经元特异性基因发生在海马神经元癫痫持续状态和创伤性脑损伤后，在这些动物癫痫的后续发展。这些被抑制的基因中最主要的是神经递质受体。这些基因表达的下调在损伤后持续7-10天，并破坏海马功能。这反过来可能有助于癫痫的长期发展。在这个建议中，我们将确定是否钝化这种神经元特异性基因的转录抑制将阻止损伤的长期病理结果，包括癫痫。组蛋白去乙酰化酶抑制剂已被开发为转录去抑制剂，并显示出作为抗癌药物的前景。该建议的中心假设是，通过给予组蛋白去乙酰化酶抑制剂来阻止损伤诱导的神经递质受体基因表达抑制是阻断获得性癫痫潜在疾病过程的可行治疗策略。旨在检验我们中心假设的研究将集中在2个具体目标上：具体目标1。评估CNS损伤后海马齿状核细胞中转录去阻遏物对神经递质受体下调的影响。具体目标2。确定转录去阻遏物是否会阻断中枢神经系统损伤的主要长期病理后遗症之一：癫痫。使用电生理，分子和整个动物的方法相结合，本建议将直接评估的潜力，转录去阻遏物作为新的治疗药物在癫痫的控制。由于许多此类药物目前已被批准为抗癌药物和一线抗惊厥药物，因此该提案的积极初步数据有可能迅速进入临床，作为阻断或延缓获得性癫痫发展的潜在疾病过程的可行策略。.

DESCRIPTION (provided by applicant): Status epilepticus and other injurious stimuli to the CNS like traumatic brain injury trigger a variety of responses in hippocampal neurons. We have recently described an acute transcriptional repression of a broad array of neuron-specific genes which occurs in hippocampal neurons of rats following status epilepticus and traumatic brain injury, prior to the subsequent development of epilepsy in these animals. Chief among these repressed genes are neurotransmitter receptors. Downregulation in expression of these genes persists for 7-10 days following injury, and disrupts hippocampal function. This in turn may contribute to the long term development of epilepsy. In this proposal, we shall determine whether blunting this transcriptional repression of neuron-specific genes will block the long-term pathological outcomes of injury, including epilepsy. Histone deacetylase inhibitors have been developed as transcriptional derepressors, and show promise as anti-cancer drugs. The CENTRAL HYPOTHESIS of this proposal is that arresting injury-induced repression of neurotransmitter receptor gene expression through administration of histone deacetylase inhibitors is a viable therapeutic strategy to block the disease process underlying acquired epilepsies. Research directed at testing our central hypothesis will focus on 2 SPECIFIC AIMS: Specific Aim 1. Assess the effects of transcriptional derepressors on neurotransmitter receptor downregulation in hippocampal dentate granule cells following CNS injury. Specific Aim 2. Determine whether transcriptional derepressors will block one of the primary, long term pathological sequelae of CNS injury: epilepsy. Using a combination of electrophysiological, molecular, and whole animal approaches, the present proposal will directly assess the potential of transcriptional derepressors as novel therapeutic agents in the control of epileptogenesis. Since many such agents are currently approved as cancer drugs and frontline anticonvulsants, positive preliminary data from this proposal has the potential to rapidly move into the clinic, as a viable strategy to block or retard the disease process underlying the development of acquired epilepsies. .