权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Inflammatory control of blood-brain barrier integrity and epileptogenesis after seizures

癫痫发作后血脑屏障完整性和癫痫发生的炎症控制

基本信息

批准号：
9914359
负责人：
RAYMOND J DINGLEDINE
金额：
$ 42.22万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-15 至 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9914359
关键词：
Ablation Acute Address Albumins Alzheimer&apos s Disease Amygdaloid structure Amyotrophic Lateral Sclerosis Animal Model Anxiety Appearance Astrocytes Autoimmune Process Behavioral Assay Blood Blood - brain barrier anatomy Blood Vessels Brain Brain Injuries Capillary Endothelial Cell Cells Chronic Cognitive deficits Conditioned Culture Media Cortical Dysplasia Cyclic AMP-Dependent Protein Kinases Development Dinoprostone Disease Down-Regulation Electroencephalography Elements Encephalitis Endothelium Epilepsy Epileptogenesis Event Exposure to Flow Cytometry Fluorescein-5-isothiocyanate Genes Genetic Gliosis In Vitro Infection Infiltration Inflammation Inflammation Mediators Inflammatory Interleukin-1 Interleukin-6 Knockout Mice Life Maintenance Measures Mediating Mediator of activation protein Messenger RNA Microglia Modeling Modification Molecular Molecular Target Morbidity - disease rate Multiple Sclerosis Mus Neurodegenerative Disorders Neurological emergencies Neurons Neutrophilic Infiltrate PTGS2 gene Pathway interactions Pharmacology Pilocarpine Play Population Principal Investigator Production Prosencephalon Prostaglandin Receptor Proteins Quantitative Reverse Transcriptase PCR Reaction Refractory Rodent Role Seizures Series Serum Albumin Signal Pathway Status Epilepticus Stroke TNF gene Testing Up-Regulation Vascular Endothelial Cell Western Blotting Work aging brain arrestin 1 arrestin 2 cell type chemokine comorbidity conditional knockout cyclooxygenase 2 cytokine design in vitro Model in vivo interest kainate malformation man monocyte mouse model neuroinflammation neutralizing antibody novel object recognition prevent programs receptor recruit small molecule tool

项目摘要

Project Summary Accumulating evidence in animal models highlights that inflammation ensuing in the brain during status epilepticus (SE) may play a determinant role in ongoing seizures and their long-term detrimental consequences, independent of an infection or auto-immune cause. Studies in a multitude of animal models demonstrate that SE causes a rapid and intense inflammatory cascade in the forebrain involving interactions among neurons, reactive astrocytes, activated microglia, vascular endothelial cells and, eventually, infiltrating neutrophils and monocytes from the blood. The pathophysiological interactions among the various inflammatory molecules, and the sequence of events leading to their induction, have not yet been dissected. The broad cytokine burst and gliosis following SE is blunted in mice that have genetic ablations of COX-2 restricted to those principal forebrain neurons in which COX-2 is normally induced by SE, pointing to a role for COX-2 pathways in SE-induced inflammation including breakdown of the blood-brain barrier (BBB), which is sufficient to produce epilepsy. Previous work showed that the EP2 receptor mediates much of the COX-2 effect. We hypothesize that SE-related morbidity is largely due to activation of microglial EP2 receptors, which modulates production of cytokines that degrade the BBB. Our specific aims are: 1. To test the hypothesis that activated microglia rather than inflammatory monocytes are responsible for EP2- regulated BBB breakdown after seizures; 2. To test the hypothesis that IL- -secreted mediator and Epac the major EP2 signaling pathway that degrades the integrity of the blood-brain barrier after SE; 3. To determine whether EP2 activation plays a dominant role in the development of epilepsy or its comorbidities after SE. To address these aims we employ in vitro culture models of the BBB and in vivo SE models with cell- specific conditional knockouts of EP2. Immunohistochemical, western blot, FACS, qRT-PCR, EEG and behavioral assays are performed.

项目总结