Prostaglandin signaling following seizures

癫痫发作后的前列腺素信号传导

• 批准号: 9755011
• 负责人: Jianxiong Jiang
• 金额: $ 19万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-03 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9755011
• 关键词: Prostaglandin; signaling; following; seizures; Prostaglandin; signaling; following; seizures

Project Summary/Abstract As the third most prevalent brain disorder, epilepsy affects virtually three million Americans and results in an estimated annual health care cost of $17.6 billion. There are about 150,000 new cases of epilepsy annually diagnosed in the U.S., mostly in children and the elderly. Current antiepileptic drugs (AEDs) dampen seizures mainly via enhancing GABA function or blocking sodium channels. However, the conventional AEDs cause well-documented side effects and lack efficacy in about a third of epilepsy patients. In addition, no current drug has been shown to prevent epileptogenesis, i.e., the development of epilepsy after acute brain insults. Identifying new drug targets and developing novel therapies are urgently needed to achieve the ultimate goal of “no seizures, no side effects” in the management of epilepsy. We previously demonstrated that prostaglandin E2 (PGE2) via its EP2 receptor subtype plays essential roles in prolonged seizure-induced neuroinflammation and neurodegeneration. We also found that EP2 receptor regulates the expression of a variety of pro-inflammatory genes in microglia likely via cAMP/Epac signaling. A better understanding of inflammatory prostaglandin signaling pathways that contribute to the pathophysiology of seizures and epilepsy might help identify novel drug targets with more specificity. In this proposal, we will test the hypothesis that prostaglandin PGE2 receptor EP2 in microglia mediates seizure-provoked brain inflammation and injury through cAMP/Epac signaling. We will utilize a combination of novel molecular genetics, pharmacology and behavior strategies that we developed in our laboratory to test this hypothesis in rodent models of epilepsy. Successful completion of these studies will provide new insights into the regulation of inflammation and injury in epileptic brain that should be also relevant to many other acute or chronic neurological conditions involving neuroinflammation with elevated COX-2 and PGE2 activities, including stroke, multiple sclerosis, Alzheimer's disease, Parkinson's disease, etc. More importantly, this research is expected to provide critical information that will guide drug discovery efforts aimed at developing novel therapeutic agents to treat these brain conditions.

项目摘要/摘要 作为第三种普遍的脑部疾病，癫痫影响几乎有300万美国人， 导致估计的年度医疗保健费用为176亿美元。大约有15万个新 每年在美国诊断出癫痫病例，主要是儿童和年龄较大的病例。当前的 抗癫痫药（AED）该死的癫痫发作主要是通过增强GABA功能或阻塞 钠通道。但是，常规AED会引起有据可查的副作用， 大约三分之一的癫痫患者缺乏效率。另外，目前尚未证明 防止癫痫发生，即急性脑感染后癫痫发育。识别 迫切需要新的药物靶标和开发新型疗法以实现最终 癫痫管理中“无癫痫发作，无副作用”的目标。我们以前 证明前列腺素E2（PGE2）通过其EP2受体亚型在 长时间癫痫发作引起的神经炎症和神经变性。我们还发现EP2 受体调节小胶质细胞中各种促炎基因的表达可能是通过 营地/EPAC信号。更好地了解炎症前列腺素信号通路 这有助于癫痫病和癫痫病的病理生理学，可能有助于识别新的药物 具有更特异性的目标。在此提案中，我们将检验前列腺素的假设 小胶质细胞中的PGE2受体EP2介导癫痫发作的脑感染和损伤 通过营地/EPAC信号传导。我们将利用新型分子遗传学的结合， 我们在实验室中制定的药理学和行为策略以对此进行测试 癫痫啮齿动物模型中的假设。这些研究的成功完成将提供 对癫痫大脑感染和损伤调节的新见解也应 与许多其他急性或年代神经系统疾病有关，涉及神经炎症与 COX-2和PGE2活动升高，包括中风，多发性硬化症，阿尔茨海默氏病， 帕金森氏病等。更重要的是，这项研究有望提供关键 将指导旨在开发新型治疗剂的药物发现工作的信息 治疗这些大脑条件。