Prostaglandin signaling following seizures

癫痫发作后的前列腺素信号传导

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要作为第三种最常见的脑部疾病，癫痫症影响着近 300 万美国人预计每年新增约 150,000 人的医疗保健费用为 176 亿美元。美国每年诊断出癫痫病例，其中大多数是儿童和老年人。抗癫痫药物 (AED) 主要通过增强 GABA 功能或阻断来抑制癫痫发作然而，传统的 AED 会引起有据可查的副作用。此外，目前还没有药物被证明对大约三分之一的癫痫患者有效。预防癫痫发生，即急性脑损伤后癫痫的发展。迫切需要新的药物靶点和开发新疗法以实现最终目标我们之前的癫痫治疗目标是“无癫痫发作，无副作用”。证明前列腺素 E2 (PGE2) 通过其 EP2 受体亚型在我们还发现 EP2 会导致长期癫痫发作引起的神经炎症和神经变性。受体调节小胶质细胞中多种促炎基因的表达，可能通过更好地了解炎症前列腺素信号通路。有助于癫痫发作和癫痫的病理生理学的研究可能有助于识别新药物在本提案中，我们将测试前列腺素的假设。小胶质细胞中的 PGE2 受体 EP2 介导癫痫诱发的脑部炎症和损伤通过 cAMP/Epac 信号传导，我们将利用新型分子遗传学的组合，我们在实验室开发的药理学和行为策略来测试这一点成功完成这些研究将提供癫痫啮齿动物模型的假设。关于癫痫大脑炎症和损伤调节的新见解也应该与许多其他涉及神经炎症的急性或慢性疾病有关 COX-2 和 PGE2 活性升高，包括中风、多发性硬化症、阿尔茨海默病、帕金森病等。更重要的是，这项研究有望提供关键的指导旨在开发新型治疗药物的药物发现工作的信息来治疗这些大脑疾病。