Transcriptional Repression Therapeutic Target/Epilepsy

转录抑制治疗靶点/癫痫

• 批准号: 6984334
• 负责人: DOUGLAS A COULTER
• 金额: $ 19.19万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6984334
• 关键词: amidohydrolases; anticonvulsants; brain disorder chemotherapy; brain electrical activity; brain injury; butyrates; disease /disorder model; drug screening /evaluation; electrophysiology; enzyme inhibitors; epilepsy; generalized seizures; genetic regulation; genetic transcription; granule cell; hippocampus; laboratory rat; neurochemistry; neurogenetics; neuroprotectants; neurotransmitter receptor; nonhuman therapy evaluation; valproate; videotape /videodisc

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. .

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伤害性刺激（如创伤性脑损伤）会引发海马神经元的各种反应。我们最近描述了一系列神经元特异性基因的急性转录抑制，这种抑制发生在癫痫持续状态和创伤性脑损伤后的大鼠海马神经元中，随后这些动物发生癫痫之前。这些被抑制的基因中最主要的是神经递质受体。这些基因的表达下调在受伤后持续 7-10 天，并破坏海马功能。这反过来可能会导致癫痫的长期发展。在本提案中，我们将确定削弱神经元特异性基因的转录抑制是否会阻止损伤（包括癫痫）的长期病理结果。组蛋白脱乙酰酶抑制剂已被开发为转录去阻遏剂，并显示出作为抗癌药物的前景。该提案的中心假设是，通过施用组蛋白脱乙酰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止获得性癫痫疾病进程的可行治疗策略。旨在检验我们的中心假设的研究将集中于 2 个具体目标： 具体目标 1. 评估转录去阻遏剂对中枢神经系统损伤后海马齿状颗粒细胞中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。通过结合电生理学、分子学和整体动物方法，本提案将直接评估转录去阻遏剂作为控制癫痫发生的新型治疗剂的潜力。由于许多此类药物目前已被批准作为癌症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，作为阻止或延缓获得性癫痫发展的疾病过程的可行策略。 。