Javits Award Final Three Years

贾维茨奖最后三年

基本信息

批准号：
10809208
负责人：
Karen S Wilcox
金额：
$ 38.48万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10809208
关键词：
Acute Animal Model Award Brain C57BL/6 Mouse Calcium Cell Death Central Nervous System Infections Central Nervous System Viral Diseases Chronic Cytokine Receptors Data Development Electroencephalography Electrophysiology (science)Epilepsy Epileptogenesis Generations Hippocampus Image Immune In Vitro Infection Infection prevention Injections Knock-out Microglia Monitor Mus Necrosis Neurons Pathologic Pathway interactions Patients Process Production Proteins Recurrence Research Risk Role Seizures Signal Transduction Slice Status Epilepticus Synaptic Transmission System TMEV TNF gene Temporal Lobe Epilepsy Testing Time Transgenic Mice Viral Virus Diseases acute infection cell motility cytokine experimental study in vivo ineffective therapies innovation insight interdisciplinary approach mouse model novel novel therapeutic intervention receptor selective expression tumor two photon microscopy two-photon

项目摘要

PROJECT SUMMARY: Viral infections of the central nervous system (CNS) are associated with an increased risk for seizures, status epilepticus (SE), and the development of chronic epilepsy. Our collaborative group has developed the first animal model of viral-induced epilepsy. Mice (C57BL/6) who receive intra-cerebral injections of Theiler's Murine Encephalomyelitis Virus (TMEV) display acute spontaneous seizures several days after infection, survive the initial infection and go on to develop spontaneous recurrent seizures. Furthermore, our data from the last award period using C57BL/6 mice with various cytokines or cytokine receptors knocked-out have shown that manipulations in the TNFα system can significantly alter the pathologic sequelae observed following TMEV injection. Therefore, we propose to test our overall hypothesis that following TMEV infection, calcium dependent increases in production and release of TNFα from microglia activates the neuronal TNFαR1 pathway, contributing to seizure generation. The proposed experiments will lead to a greater understanding of the role of viral and immune contributions to acute seizures, altered neuronal and microglial function, and epileptogenesis. We will use a multidisciplinary approach to test our hypothesis, including, state of the art in vivo and in vitro 2 photon microscopy, calcium imaging, novel transgenic mouse models, chronic video-EEG monitoring and brain slice electrophysiology to: 1) Determine the time course and extent of physical changes, motility, and the development of spontaneous calcium transients in microglia in TMEV infected mice during the acute infection period using GCAMP5G selectively expressed in microglia; 2) Determine the mechanisms underlying calcium transients in activated microglia during the acute infection period and the role of calcium transients in cytokine production; and 3) Determine if signaling through the neuronal TNFαR1 pathway underlies hippocampal excitability and seizure activity following TMEV infection. We anticipate that these experiments will provide important new insight into the role of TNFα and it's receptor, TNFαR1 in cell death, synaptic transmission and epileptogenesis and set the stage for the development of novel therapeutic interventions for the prevention of infection induced epilepsy.

项目摘要：中枢神经系统 (CNS) 的病毒感染与病毒感染增加有关我们的合作小组研究了癫痫发作、癫痫持续状态 (SE) 和慢性癫痫发展的风险。开发了第一个接受脑内注射的病毒诱发癫痫小鼠模型（C57BL/6）。注射泰勒氏鼠脑脊髓炎病毒 (TMEV) 会导致急性自发性癫痫发作感染后几天，从最初的感染中幸存下来，并继续发展为自发性复发性癫痫发作。此外，我们使用具有各种细胞因子或细胞因子的 C57BL/6 小鼠在上一个奖励期获得的数据受体敲除表明，TNFα系统的操作可以显着改变病理学因此，我们建议检验我们的总体假设： TMEV 感染后，小胶质细胞中 TNFα 的产生和释放依赖钙依赖性增加激活神经元 TNFαR1 通路，有助于癫痫发作。更好地了解病毒和免疫对急性癫痫发作的作用，我们将使用多学科方法来测试我们的神经元和小胶质细胞功能以及癫痫发生。假设，包括体内和体外最先进的 2 光子显微镜、钙成像、新颖转基因小鼠模型、慢性视频脑电图监测和脑切片电生理学：1) 确定身体变化、运动和自发钙瞬变发展的时间过程和程度使用 GCAMP5G 在急性感染期间选择性表达的 TMEV 感染小鼠的小胶质细胞中小胶质细胞；2）确定急性期激活小胶质细胞钙瞬变的机制感染期和钙瞬变在细胞因子产生中的作用；3) 确定信号传导是否通过神经元 TNFαR1 通路是 TMEV 后海马兴奋性和癫痫发作活动的基础我们预计这些实验将为 TNFα 及其作用提供重要的新见解。受体、TNFαR1 在细胞死亡、突触传递和癫痫发生中的作用，并为开发新的治疗干预措施来预防感染诱发的癫痫。