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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.

项目总结/摘要作为第三大最普遍的大脑疾病，癫痫影响了近300万美国人，估计每年的医疗保健成本为176亿美元。大约有15万新的美国每年确诊的癫痫病例，主要是儿童和老人。电流抗癫痫药物（AEDs）主要通过增强GABA功能或阻断GABA受体来抑制癫痫发作，钠离子通道然而，传统的AED会引起有据可查的副作用，对大约三分之一的癫痫患者缺乏疗效。此外，目前还没有任何药物显示预防癫痫发生，即，急性脑损伤后癫痫的发展。识别迫切需要新的药物靶点和开发新的治疗方法，以实现最终的在癫痫的管理中实现“无癫痫发作，无副作用”的目标。我们之前研究表明，前列腺素E2（PGE 2）通过其EP 2受体亚型在延长的脑缺血诱导的神经炎症和神经变性。我们还发现EP 2 受体调节小胶质细胞中多种促炎基因的表达，可能通过 cAMP/Epac信号传导。更好地了解炎症性前列腺素信号通路有助于癫痫发作和癫痫的病理生理学可能有助于识别新药目标更加明确。在这个提议中，我们将检验前列腺素小胶质细胞PGE 2受体EP 2介导脑损伤和炎症反应通过cAMP/Epac信号传导。我们将利用新型分子遗传学，我们在实验室开发的药理学和行为策略，癫痫模型的假设。成功完成这些研究将提供对癫痫脑中炎症和损伤的调节的新见解，也应该是与许多其他涉及神经炎症的急性或慢性神经系统疾病相关，升高的考克斯-2和PGE 2活性，包括中风、多发性硬化、阿尔茨海默病，更重要的是，这项研究有望提供关键的信息将指导药物发现工作，旨在开发新的治疗剂来治疗这些脑部疾病